Solid forms of an n-terminal domain androgen receptor inhibitor and uses thereof

ABSTRACT

The present invention relates to a crystalline form of Compound I, a salt, a solvate, or a solvate salt thereof or an amorphous form of Compound I, a salt, a solvate, or a solvate salt thereof. The present invention also provides compositions comprising the crystalline form and/or the amorphous form, therapeutic uses of the crystalline forms and/or the amorphous forms, and the compositions thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/011,671, filed Apr. 17, 2020, the disclosure of which is incorporatedby reference herein in its entirety.

FIELD OF THE INVENTION

The present disclosure relates to solid forms of Compound I or apharmaceutically acceptable salt and/or solvate thereof, pharmaceuticalcompositions comprising the crystalline form, and therapeutic usesthereof. In particular, the present disclosure relates to solid forms ofCompound I or a pharmaceutically acceptable salt and/or solvate thereof,which are useful for treating various diseases, including cancers suchas prostate cancer.

BACKGROUND OF THE INVENTION

Androgens mediate their effects through the androgen receptor (AR).Androgens play a role in a wide range of developmental and physiologicalresponses and are involved in male sexual differentiation, maintenanceof spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A.Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E.Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361(1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K.Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Several lines ofevidence show that androgens are associated with the development ofprostate carcinogenesis. Firstly, androgens induce prostaticcarcinogenesis in rodent models (R. L. Noble, Cancer Res 37, 1929-1933(1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receivingandrogens in the form of anabolic steroids have a higher incidence ofprostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986);J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149,2365-2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D.Alrenga & I. M. Bush, Am J Surg 131, 599-600 (1976)). Secondly, prostatecancer does not develop if humans or dogs are castrated before puberty(J. D. Wilson & C. Roehrborn, J Clin Endocrinol Metab 84, 4324-4331(1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adultmales causes involution of the prostate and apoptosis of prostaticepithelium while eliciting no effect on other male external genitalia(E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000);J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgensprovides the underlying rationale for treating prostate cancer withchemical or surgical castration also known as androgen ablation therapy(ABT) or androgen deprivation therapy (ADT).

Androgen receptor (AR) is a transcription factor that plays dual rolesin breast cancer cells: promoting or inhibiting proliferation dependingon expression and activity of estrogen receptor-alpha. Expression of ARis detected in up to 90% of all breast cancers.

Androgens also play a role in female diseases such as polycystic ovarysyndrome as well as cancers. One example is ovarian cancer whereelevated levels of androgens are associated with an increased risk ofdeveloping ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon,C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274,1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, BrCancer 86, 879-885 (2002)). The AR has been detected in a majority ofovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998);B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton &W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogenreceptor-alpha (ERa) and the progesterone receptor are detected in lessthan 50% of ovarian tumors.

The only effective treatment available for advanced prostate cancer isthe withdrawal of androgens which are essential for the survival ofprostate luminal cells. Androgen ablation therapy causes a temporaryreduction in tumor burden concomitant with a decrease in serumprostate-specific antigen (PSA). Unfortunately, prostate cancer caneventually grow again in the absence of testicular androgens(castration-resistant disease) (Huber et al 1987 Scand J. Urol Nephrol.104, 33-39). Castration-resistant prostate cancer that is still drivenby AR is biochemically characterized before the onset of symptoms by arising titre of serum PSA (Miller et al 1992 J. Urol. 147, 956-961).Once the disease becomes castration-resistant most patients succumb totheir disease within two years.

The AR has distinct functional domains that include the carboxy-terminalligand-binding domain (LBD), a DNA-binding domain (DBD) comprising twozinc finger motifs, and an N-terminus domain (NTD) that contains twotranscriptional activation units (tau1 and tau5) within activationfunction-1 (AF-1). Binding of androgen (ligand) to the LBD of the ARresults in its activation such that the receptor can effectively bind toits specific DNA consensus site, termed the androgen response element(ARE), on the promoter and enhancer regions of “normally” androgenregulated genes, such as PSA, to initiate transcription. The AR can beactivated in the absence of androgen by stimulation of thecAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6)and by various growth factors (Culig et al 1994 Cancer Res. 54,5474-5478; Nazareth et al 19961 Biol. Chem. 271, 19900-19907; Sadar 1999J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277,7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094). Themechanism of ligand-independent transformation of the AR has been shownto involve: 1) increased nuclear AR protein suggesting nucleartranslocation; 2) increased AR/ARE complex formation; and 3) the AR-NTD(Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J Biol.Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277,38087-38094). The AR can be activated in the absence of testicularandrogens by alternative signal transduction pathways incastration-resistant disease, which is consistent with the finding thatnuclear AR protein is present in secondary prostate cancer tumors (Kimet al 2002 Am. J. Pathol. 160, 219-226; and van der Kwast et al 1991Inter. J. Cancer 48, 189-193).

Clinically available inhibitors of the AR include nonsteroidalantiandrogens such as bicalutamide (Casodex™), nilutamide, flutamide,and enzalutamide. There is also a class of steroidal antiandrogens, suchas cyproterone acetate and spironolactone. Both steroidal andnon-steroidal antiandrogens target the LBD of the AR and predominantlyfail presumably due to poor affinity and mutations that lead toactivation of the AR by these same antiandrogens (Taplin, M. E., Bubley,G. J., Kom Y. J., Small E. J., Uptonm M., Rajeshkumarm B., Balkm S. P.,Cancer Res., 59, 2511-2515 (1999)), and constitutively active AR splicevariants. Antiandrogens have no effect on the constitutively active ARsplice variants that lack the ligand-binding domain (LBD) and areassociated with castration-recurrent prostate cancer (Dehm S M, SchmidtL J, Heemers H V, Vessella R L, Tindall D J., Cancer Res 68, 5469-77,2008; Guo Z, Yang X, Sun F, Jiang R, Linn D E, Chen H, Chen H, Kong X,Melamed J, Tepper C G, Kung H J, Brodie A M, Edwards J, Qiu Y., CancerRes. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16-22; Sun et al2010 J Clin Invest. 2010 120, 2715-30) and resistant to abiraterone andenzalutamide (Antonarakis et al., N Engl J Med. 2014, 371, 1028-38;Scher et al JAMA Oncol. 2016 doi: 10.1001). Conventional therapy hasconcentrated on androgen-dependent activation of the AR through itsC-terminal domain.

Other relevant AR antagonists previously reported (see, WO 2010/000066,WO 2011/082487; WO 2011/082488; WO 2012/145330; WO 2015/031984; WO2016/058080; and WO 2016/058082) that bind to full-length AR and/ortruncated AR splice variants that are currently being developed include:AR degraders such as niclosamide (Liu C et al 2014), galeterone (Njar etal 2015; Yu Z at al 2014), and ARV-330/Androgen receptor PROTAC (Neklesaet al 2016 J Clin Oncol 34 suppl 2S; abstr 267); AR DBD inhibitorVPC-14449 (Dalal K et al 2014 J Biol Chem. 289(38):26417-29; Li H et al2014 J Med Chem. 57(15):6458-67); antiandrogens apalutamide (Clegg N Jet al 2012), ODM-201 (Moilanen A M et al 2015), ODM-204 (Kallio et al JClin Oncol 2016 vol. 34 no. 2 suppl 230), TAS3681 (Minamiguchi et al2015 J Clin Oncol 33, suppl 7; abstr 266); and AR NTD inhibitors3E10-AR441bsAb (Goicochea N L et al 2015), and sintokamide (Sadar et al2008; Banuelos et al 2016).

The AR-NTD is also a target for drug development (e.g. WO 2000/001813;Myung et al. J. Clin. Invest 2013, 123, 2948), since the NTD containsActivation-Function-1 (AF-1) which is the essential region required forAR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5,1396-404). The AR-NTD importantly plays a role in activation of the ARin the absence of androgens (Sadar, M. D. 1999 J. Biol. Chem. 274,7777-7783; Sadar M D et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda etal 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem. 277,38087-38094; Blaszczyk et al 2004 Clin Cancer Res. 10, 1860-9; Dehm etal 2006 J Biol Chem. 28, 27882-93; Gregory et al 2004 J Biol Chem. 279,7119-30). The AR-NTD is important in hormonal progression of prostatecancer as shown by application of decoy molecules (Quayle et al 2007,Proc Natl Acad Sci USA. 104, 1331-1336).

While the crystal structure has been resolved for the AR C-terminus LBD,this has not been the case for the NTD due to its high flexibility andintrinsic disorder in solution (Reid et al 2002 J. Biol. Chem. 277,20079-20086) thereby hampering virtual docking drug discoveryapproaches. Compounds that modulate AR, potentially through interactionwith NTD domain, include the bisphenol compounds disclosed in publishedPCT Nos: WO 2010/000066, WO 2011/082487; WO 2011/082488; WO 2012/145330;WO 2012/139039; WO 2012/145328; WO 2013/028572; WO 2013/028791; WO2014/179867; WO 2015/031984; WO 2016/058080; WO 2016/058082; WO2016/112455; WO 2016/141458; WO 2017/177307; WO 2017/210771; WO2018/045450; WO 2019/226991; WO 2020/081999; and WO 2020/198710; whichare hereby incorporated by reference in their entireties.

Transcriptionally active androgen receptor plays a major role in CRPC inspite of reduced blood levels of androgen (Karantanos, T. et al Oncogene2013, 32, 5501-5511; Harris, W. P. et al Nature Clinical PracticeUrology, 2009, 6, 76-85). AR mechanisms of resistance to ADT include:overexpression of AR (Visakorpi, T. et al Nature Genetics 1995, 9,401-406; Koivisto, P. et al Scandinavian Journal of Clinical andLaboratory Investigation Supplementum 1996, 226, 57-63);gain-of-function mutations in the AR LBD (Culig Z. et al MolecularEndocrinology 1993, 7, 1541-1550); intratumoral androgen synthesis (Cai,C. et al Cancer Research 2011, 71, 6503-6513); altered expression andfunction of AR coactivators (Ueda, T. et al The Journal of BiologicalChemistry 2002, 277, 38087-38094; Xu J. et al Nature Reviews Cancer2009, 9, 615-630); aberrant post-translational modifications of AR(Gioeli D. et al Molecular and Cellular Endocrinology 2012, 352, 70-78;van der Steen T. et al International Journal of Molecular Sciences 2013,14, 14833-14859); and expression of AR splice variants (AR-Vs) whichlack the ligand-binding domain (LBD) (Karantanos, T. et al Oncogene2013, 32, 5501-5511; Andersen R. J. et al Cancer Cell 2010, 17, 535-546;Myung J. K. et al The Journal of Clinical Investigation 2013, 123,2948-2960; Sun S. et al The Journal of Clinical Investigation 2010, 120,2715-2730). Anti-androgens such as bicalutamide and enzalutamide targetAR LBD, but have no effect on truncated constitutively active AR-Vs suchas AR-V7 (Li Y. et al Cancer Research 2013, 73, 483-489). Expression ofAR-V7 is associated with resistance to current hormone therapies (Li Y.et al Cancer Research 2013, 73, 483-489; Antonarakis E. S. et al The NewEngland Journal of Medicine 2014, 371, 1028-1038).

SUMMARY OF THE INVENTION

The present disclosure relates to a crystalline form of an androgenreceptor modulator, Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof.

In one embodiment, Compound I is an androgen receptor N-terminal domaininhibitor.

The present disclosure relates to a crystalline form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof. Inone embodiment, the crystalline form is anhydrous or non-solvated. Inone embodiment of the crystalline form, Compound I is not present as apharmaceutically acceptable salt.

In one embodiment of the present disclosure, the crystalline form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof exhibits an X-ray powder diffraction (XRPD) patterncomprising peaks at about 17.48±0.2, 20.78±0.2, and 21.80±0.2 degreestwo-theta. In one embodiment, the XRPD pattern further comprises peaksat about 5.19±0.2 and 12.94±0.2 degrees two-theta. In one embodiment,the XRPD pattern further comprises at least two peaks selected fromabout 17.80±0.2, 18.74±0.2, 19.57±0.2, 22.59±0.2, 25.28±0.2, or29.95±0.2 degrees two-theta.

In one embodiment of the present disclosure, the crystalline form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof exhibits an XRPD pattern comprising peaks in Table 1B. Inone embodiment, the XRPD peaks at about 5.19±0.2, 12.94±0.2, 17.48±0.2,20.78±0.2, and 21.80±0.2 degrees two-theta have peak intensities of atleast 35%.

In one embodiment of the present disclosure, the crystalline form ofCompound I is Form A exhibiting an XRPD pattern substantially similar toFIG. 1, provided that peaks at 27.3±0.2 and 31.7±0.2 degrees two-thetaare excluded.

In one embodiment of the present disclosure, the crystalline form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof exhibits a differential scanning calorimetry (DSC)thermogram comprising an endotherm peak which onset at about 182° C.

In one embodiment of the present disclosure, the crystalline form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof exhibits a thermogravimetric analysis (TGA) thermogramcomprising a change in slope which onset at about 284° C.

In one embodiment of the present disclosure, the crystalline form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof has a purity in the range of about 80% to about 99%. In oneembodiment of the present disclosure, the crystalline form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereofhas a purity of about 95% or higher. In one embodiment, the crystallineform has a purity of about 97% or higher. In one embodiment, thecrystalline form has a purity of about 99% or higher.

The present disclosure relates to an amorphous form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof. Inone embodiment, the amorphous form is anhydrous or non-solvated. In oneembodiment of the amorphous form, Compound I is not present as apharmaceutically acceptable salt. In another embodiment, the amorphousform of Compound I or a pharmaceutically acceptable salt, solvate, orsolvate salt thereof is in a pharmaceutical composition. In a specificembodiment, the pharmaceutical composition comprises Compound I in asolid dispersion.

In one embodiment of the present disclosure, the amorphous form ofCompound I exhibits an XRPD pattern substantially similar to FIG. 7(third spectrum from bottom), provided that peaks at 27.3±0.2 and31.7±0.2 degrees two-theta are excluded.

The present disclosure relates to an amorphous form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof whichexhibits a differential scanning calorimetry (DSC) thermogram comprisingan exotherm peak at about 91° C. In one embodiment, the amorphous formexhibits a differential scanning calorimetry (DSC) thermogram comprisingan endotherm peak which onset at about 178° C.

The present disclosure relates to an amorphous form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof whichexhibits a glass transition temperature at about 61° C.

The present disclosure relates to an amorphous form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof whichexhibits a thermogravimetric analysis (TGA) thermogram comprising achange in slope which onset at about 280° C.

In one embodiment of the present disclosure, the amorphous form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof has a purity in the range of about 80% to about 99%. In oneembodiment of the present disclosure, the amorphous form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereofhas a purity of about 95% or higher. In one embodiment, the amorphousform has a purity of about 97% or higher. In one embodiment, theamorphous form has a purity of about 99% or higher.

The present disclosure also relates to a composition comprising any oneof the crystalline forms or the amorphous forms of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof asdisclosed herein, and a pharmaceutically acceptable carrier.

In one embodiment, the compositions disclosed herein comprises acrystalline form is Form A. In one embodiment, the composition furthercomprises an amorphous form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof.

In one embodiment, any one of the compositions disclosed herein canfurther comprising an additional therapeutic agent. In one embodiment,any one of the compositions disclosed herein can further comprising oneor more additional therapeutic agents.

The present disclosure also relates to a method for treating cancercomprising administering any one of the crystalline forms or theamorphous forms of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof as disclosed herein. In one embodiment,the cancer is selected from prostate cancer, breast cancer, ovariancancer, bladder cancer, pancreatic cancer, hepatocellular cancer,endometrial cancer, or salivary gland carcinoma. In one embodiment, thecancer is prostate cancer. In one embodiment, the prostate cancer isprimary or localized prostate cancer, locally advanced prostate cancer,recurrent prostate cancer, advanced prostate cancer, metastatic prostatecancer, non-metastatic castration-resistant prostate cancer, metastaticcastration-resistant prostate cancer, and hormone-sensitive prostatecancer. In one embodiment, the prostate cancer is metastaticcastration-resistant prostate cancer. In one embodiment, the prostatecancer expresses full-length androgen receptor or truncated androgenreceptor splice variant.

The present disclosure also relates to a method for modulating androgenreceptor activity, administering any one of the crystalline forms or theamorphous forms of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof as disclosed herein. In one embodiment,the modulating androgen receptor activity is for treating a condition ordisease selected from prostate cancer, breast cancer, ovarian cancer,bladder cancer, pancreatic cancer, hepatocellular cancer, endometrialcancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovariancysts, polycystic ovary disease, precocious puberty, spinal and bulbarmuscular atrophy, or age-related macular degeneration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows X-ray powder diffraction (XRPD) spectrum of crystallineForm A of Compound I.

FIG. 2 shows thermogravimetric analysis (TGA)/differential scanningcalorimetry (DSC) thermograms of crystalline Form A of Compound I.

FIG. 3 shows dynamic vapor sorption (DVS) profile of crystalline Form Aof Compound I.

FIG. 4 shows XRPD spectrum overlay of Compound I in crystalline Form A,Material C with crystalline Form A, Material B, and Material D.

FIG. 5 shows thermogravimetric analysis (TGA)/differential scanningcalorimetry (DSC) thermograms of Material D of Compound I.

FIG. 6 shows XRPD spectrum overlay of Compound I in crystalline Form A,Material D before drying, and Material D after drying under vacuum at50-52° C. for 3 days.

FIG. 7 shows XRPD spectrum overlay of NaCl, amorphous form of CompoundI, disordered Form A of Compound I, and disordered form of Compound I.

FIG. 8 shows a temperature modulated DSC thermogram of an amorphous formof Compound I.

FIG. 9 shows a TGA thermogram of an amorphous form of Compound I.

FIG. 10 shows XRPD spectrum overlay of disordered Form A and Form Aobtained from crystallization experiments of amorphous and disorderedCompound I.

FIG. 11 shows XRPD spectrum overlay of Form A of Compound obtainedexperimentally and calculated pattern of Form A from single crystaldata.

FIG. 12 shows individual tumor volume change from baseline measured atthe end of experiment for oral administration of representativecompounds to male NCG mice bearing LNCaP tumors

FIG. 13 shows XRPD spectrum overlay of SDD compositions A-E and Form Aof Compound I.

FIG. 14 shows modulated DSC thermogram overlay of SDD compositions A-Eof Compound I.

FIG. 15 shows XRPD spectrum overlay of SDD compositions H-J and N-RCompound I.

FIG. 16 shows solubility of amorphous form of Compound I.

DETAILED DESCRIPTION

All publications, patents and patent applications, including anydrawings and appendices therein are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent or patent application, drawing, or appendix wasspecifically and individually indicated to be incorporated by referencein its entirety for all purposes.

Definitions

While the following terms are believed to be well understood by one ofordinary skill in the art, the following definitions are set forth tofacilitate explanation of the presently disclosed subject matter.

Compound I isN-{4-[(4-{2-[3-chloro-4-(2-chloroethoxy)-5-cyanophenyl]propan-2-yl}phenoxy)methyl]pyrimidin-2-yl}methanesulfonamidehaving the structure shown below. Compound I is disclosed in WO2020/081999, which is hereby incorporated by reference in its entirety.In one embodiment, Compound I is an androgen receptor N-terminal domaininhibitor.

Throughout the present specification, the terms “about” and/or“approximately” may be used in conjunction with numerical values and/orranges. The term “about” is understood to mean those values near to arecited value. Furthermore, the phrases “less than about [a value]” or“greater than about [a value]” should be understood in view of thedefinition of the term “about” provided herein. The terms “about” and“approximately” may be used interchangeably.

Throughout the present specification, numerical ranges are provided forcertain quantities. It is to be understood that these ranges compriseall subranges therein. Thus, the range “from 50 to 80” includes allpossible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70,etc.). Furthermore, all values within a given range may be an endpointfor the range encompassed thereby (e.g., the range 50-80 includes theranges with endpoints such as 55-80, 50-75, etc.).

The term “a” or “an” refers to one or more of that entity; for example,“a androgen receptor modulator” refers to one or more androgen receptormodulators or at least one androgen receptor modulator. As such, theterms “a” (or “an”), “one or more” and “at least one” are usedinterchangeably herein. In addition, reference to “an inhibitor” by theindefinite article “a” or “an” does not exclude the possibility thatmore than one of the inhibitors is present, unless the context clearlyrequires that there is one and only one of the inhibitors.

As used herein, the verb “comprise” as is used in this description andin the claims and its conjugations are used in its non-limiting sense tomean that items following the word are included, but items notspecifically mentioned are not excluded. The present invention maysuitably “comprise”, “consist of”, or “consist essentially of”, thesteps, elements, and/or reagents described in the claims.

It is further noted that the claims may be drafted to exclude anyoptional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely”,“only” and the like in connection with the recitation of claim elements,or the use of a “negative” limitation.

The term “pharmaceutically acceptable salts” includes both acid and baseaddition salts. Pharmaceutically acceptable salts include those obtainedby reacting the active compound functioning as a base, with an inorganicor organic acid to form a salt, for example, salts of hydrochloric acid,sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonicacid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid,hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylicacid, mandelic acid, carbonic acid, etc. Those skilled in the art willfurther recognize that acid addition salts may be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods.

As used herein, “solvate” means a complex formed by solvation (thecombination of solvent molecules with molecules or ions of the activeagent of the present invention), or an aggregate that consists of asolute ion or molecule (the active agent of the present invention) withone or more solvent molecules. In the present invention, the preferredsolvate is hydrate. Examples of hydrate include, but are not limited to,hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. Itshould be understood by one of ordinary skill in the art that thepharmaceutically acceptable salt of the present compound may also existin a solvate form (solvate salt). The solvate is typically formed viahydration which is either part of the preparation of the presentcompound or through natural absorption of moisture by the anhydrouscompound of the present invention. Solvates including hydrates may beconsisting in stoichiometric ratios, for example, with two, three, foursalt molecules per solvate or per hydrate molecule. Another possibility,for example, that two salt molecules are stoichiometric related tothree, five, seven solvent or hydrate molecules. Solvents used forcrystallization, such as alcohols, especially methanol and ethanol;aldehydes; ketones, especially acetone; esters, e.g. ethyl acetate; maybe embedded in the crystal grating. Preferred are pharmaceuticallyacceptable solvents.

The term “treating” means one or more of relieving, alleviating,delaying, reducing, improving, or managing at least one symptom of acondition in a subject. The term “treating” may also mean one or more ofarresting, delaying the onset (i.e., the period prior to clinicalmanifestation of the condition) or reducing the risk of developing orworsening a condition.

An “effective amount” means the amount of a formulation according to theinvention that, when administered to a patient for treating a state,disorder or condition is sufficient to effect such treatment. The“effective amount” will vary depending on the active ingredient, thestate, disorder, or condition to be treated and its severity, and theage, weight, physical condition and responsiveness of the mammal to betreated.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical formulation that issufficient to result in a desired clinical benefit after administrationto a patient in need thereof.

As used herein, a “subject” can be a human, non-human primate, mammal,rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. Thesubject can be suspected of having or at risk for having a cancer, suchas prostate cancer, breast cancer, ovarian cancer, salivary glandcarcinoma, or endometrial cancer, or suspected of having or at risk forhaving acne, hirsutism, alopecia, benign prostatic hyperplasia, ovariancysts, polycystic ovary disease, precocious puberty, spinal and bulbarmuscular atrophy, or age-related macular degeneration. Diagnosticmethods for various cancers, such as prostate cancer, breast cancer,ovarian cancer, bladder cancer, pancreatic cancer, hepatocellularcancer, salivary gland carcinoma, or endometrial cancer, and diagnosticmethods for acne, hirsutism, alopecia, benign prostatic hyperplasia,ovarian cysts, polycystic ovary disease, precocious puberty, spinal andbulbar muscular atrophy, or age-related macular degeneration and theclinical delineation of cancer, such as prostate cancer, breast cancer,ovarian cancer, bladder cancer, pancreatic cancer, hepatocellularcancer, salivary gland carcinoma, or endometrial cancer, diagnoses andthe clinical delineation of acne, hirsutism, alopecia, benign prostatichyperplasia, ovarian cysts, polycystic ovary disease, precociouspuberty, spinal and bulbar muscular atrophy, or age-related maculardegeneration are known to those of ordinary skill in the art.

“Mammal” includes humans and both domestic animals such as laboratoryanimals (e.g., mice, rats, monkeys, dogs, etc.) and household pets(e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), andnon-domestic animals such as wildlife and the like.

All weight percentages (i.e., “% by weight” and “wt. %” and w/w)referenced herein, unless otherwise indicated, are measured relative tothe total weight of the pharmaceutical composition.

As used herein, “substantially” or “substantial” refers to the completeor nearly complete extent or degree of an action, characteristic,property, state, structure, item, or result. For example, an object thatis “substantially” enclosed would mean that the object is eithercompletely enclosed or nearly completely enclosed. The exact allowabledegree of deviation from absolute completeness may in some cases dependon the specific context. However, generally speaking, the nearness ofcompletion will be so as to have the same overall result as if absoluteand total completion were obtained. The use of “substantially” isequally applicable when used in a negative connotation to refer to thecomplete or near complete lack of action, characteristic, property,state, structure, item, or result. For example, a composition that is“substantially free of” other active agents would either completely lackother active agents, or so nearly completely lack other active agentsthat the effect would be the same as if it completely lacked otheractive agents. In other words, a composition that is “substantially freeof” an ingredient or element or another active agent may still containsuch an item as long as there is no measurable effect thereof.

Polymorphism can be characterized as the ability of a compound tocrystallize into different crystal forms, while maintaining the samechemical formula. A crystalline polymorph of a given drug substance ischemically identical to any other crystalline polymorph of that drugsubstance in containing the same atoms bonded to one another in the sameway, but differs in its crystal forms, which can affect one or morephysical properties, such as stability, solubility, melting point, bulkdensity, flow properties, bioavailability, etc.

As used herein, the term “solid dispersion” is a system in a solid state(as opposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components (homogenous mix).Generally, a solid dispersion formulation of a therapeutically activeagent(s) refers to a dispersion mixture of the therapeutically activeagent(s) in an inert carrier. Inert carriers can be a crystallinecarrier (such as sugars), a polymeric carrier (such as HPMCAS), or amixture of surfactants and polymers. Typically, a solid dispersion of atherapeutically active agent increases the surface area of thetherapeutically active agent and enhances drug solubility and/ordissolution rate.

The following description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed inventions, or that any publication specifically orimplicitly referenced is prior art.

Solid Forms of Compound I

In one embodiment, the present disclosure relates to solid forms ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof. In one embodiment, the solid form is for Compound I (not asalt, not a solvate, not a solvate salt). In one embodiment, the solidform is for a pharmaceutically acceptable salt of Compound I. In oneembodiment, the solid form is for a pharmaceutically acceptable solvateof Compound I. In one embodiment, the solid form is for apharmaceutically acceptable solvate salt of Compound I. In oneembodiment the solid form is amorphous or crystalline form.

In another embodiment, the amorphous form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof is ina pharmaceutical composition. In a specific embodiment, thepharmaceutical composition comprises Compound I in a solid dispersion.

In one embodiment, the solid form of Compound I is crystalline Form A.In one embodiment, the solid form of Compound I is amorphous form. Inone embodiment, the solid form of Compound I is Material B. In oneembodiment, the solid form of Compound I is Material C. In oneembodiment, the solid form of Compound I is Material D.

In one embodiment, the present disclosure relates to an isolated solidform of Compound I or a pharmaceutically acceptable salt, solvate, orsolvate salt thereof. In one embodiment, the isolated solid form is anisolated crystalline form of Compound I or a pharmaceutically acceptablesalt, solvate, or solvate salt thereof. In one embodiment, the isolatedsolid form is an isolated crystalline Form A of Compound I. In oneembodiment, the isolated solid form is an isolated amorphous form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof. In one embodiment, the isolated solid form is an isolatedamorphous form of Compound I.

In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of atleast about 75%, at least about 80%, at least about 85%, at least about90%, at least about 95%, at least about 97%, at least about 98%, or atleast about 99%. In one embodiment, the solid form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof has apurity of at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, at least about 97%, at least about98%, or at least about 99% with respect to one specific solid form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof.

In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of atleast about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%,about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%,about 91%, or about 90%. In one embodiment, the solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereofhas a purity of at least about 99.9%, about 99.8%, about 99.7%, about99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%,about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%,about 93%, about 92%, about 91%, or about 90% with respect to onespecific solid form of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof.

In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of about75% to about 99%. In one embodiment, the solid form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof has apurity of about 80% to about 99%. In one embodiment, the solid form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof has a purity of about 85% to about 99%. In one embodiment,the solid form of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof has a purity of about 90% to about 99%.In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of about95% to about 99%.

In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of about75% to about 99% with respect to one specific solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereof.In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of about80% to about 99% with respect to one specific solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereof.In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of about85% to about 99% with respect to one specific solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereof.In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of about90% to about 99% with respect to one specific solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereof.In one embodiment, the solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof has a purity of about95% to about 99% with respect to one specific solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereof.

In one embodiment, the specific solid form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof withhigh purity is crystalline Form A of Compound I. In one embodiment, thespecific solid form of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof with high purity is an amorphous formof Compound I.

In one embodiment, the present disclosure relates to solid forms ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof, wherein the solid form comprises one or more solid formsof Compound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof. In one embodiment, the solid form of the presentdisclosure comprises one or more forms selected from the groupconsisting of: crystalline Form A of Compound I, amorphous form ofCompound I, Material B of Compound I, Material C of Compound I, andMaterial D of Compound I.

Crystalline Form of Compound I

In one embodiment, the present disclosure relates to a crystalline formof Compound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof. In one embodiment, the present disclosure relates to ananhydrous or non-solvated crystalline form of Compound I or apharmaceutically acceptable salt thereof. In one embodiment, the presentdisclosure relates to an anhydrous or non-solvated crystalline form ofCompound I (not a salt). In one embodiment, the present disclosurerelates to a crystalline form of Compound I (not a salt). In oneembodiment, the present disclosure relates to a crystalline form ofCompound I, which is Form A.

In one embodiment, the crystalline forms are characterized by theinterlattice plane intervals determined by an X-ray powder diffraction(XRPD) pattern. The spectrum of XRPD is typically represented by adiagram plotting the intensity of the peaks versus the location of thepeaks, i.e., diffraction angle 20 (two-theta) in degrees. Theintensities are often given in parenthesis with the followingabbreviations: very strong=vst; strong=st; medium=m; weak=w; and veryweak=vw. The characteristic peaks of a given XRPD can be selectedaccording to the peak locations and their relative intensity toconveniently distinguish this crystalline structure from others. The %intensity of the peaks relative to the most intense peak may berepresented as I/Io.

Those skilled in the art recognize that the measurements of the XRPDpeak locations and/or intensity for a given crystalline form of the samecompound will vary within a margin of error. The values of degree 2θallow appropriate error margins. Typically, the error margins arerepresented by “±”. For example, the degree 2θ of about 17.48±0.2″denotes a range from about 17.46 to 17.50 degree 20. Depending on thesample preparation techniques, the calibration techniques applied to theinstruments, human operational variation, and etc., those skilled in theart recognize that the appropriate error of margins for a XRPD can beabout ±0.7; ±0.6; ±0.5; ±0.4; ±0.3; ±0.2; ±0.1; ±0.05; or less.

Additional details of the methods and equipment used for the XRPDanalysis are described in the Examples section.

In one embodiment, the crystalline forms are characterized byDifferential Scanning calorimetry (DSC). The DSC thermogram is typicallyexpressed by a diagram plotting the normalized heat flow in units ofWatts/gram (“W/g”) versus the measured sample temperature in degreeCelsius. The DSC thermogram is usually evaluated for extrapolated onsetand end (outset) temperatures, peak temperature, and heat of fusion. Apeak characteristic value of a DSC thermogram is often used as thecharacteristic peak to distinguish this crystalline structure fromothers.

Those skilled in the art recognize that the measurements of the DSCthermogram for a given crystalline form of the same compound will varywithin a margin of error. The values of a single peak characteristicvalue, expressed in degree Celsius, allow appropriate error margins.Typically, the error margins are represented by “±”. For example, thesingle peak characteristic value of about “17.48±0.2” denotes a rangefrom about 17.46 to 17.50. Depending on the sample preparationtechniques, the calibration techniques applied to the instruments, humanoperational variations, and etc., those skilled in the art recognizethat the appropriate error of margins for a single peak characteristicvalue can be ±2.5; ±2.0; ±1.5; ±1.0; ±0.5; or less.

Additional details of the methods and equipment used for the DSCthermogram analysis are described in the Examples section.

In one embodiment, the crystalline forms are characterized by DynamicVapor Sorption (DVS). The DVS profile is typically expressed by adiagram plotting the sample relative humidity (RH) versus the change inmass (%). The DVS profile provides information on hygroscopicity of thecrystalline form at different RH conditions.

Additional details of the methods and equipment used for DVS aredescribed in the Examples section.

In one embodiment, the present disclosure relates to Form A, which is acrystalline form of Compound I that is anhydrous or non-solvated. In oneembodiment, Form A is more stable than other crystalline forms ofCompound I, pharmaceutically acceptable salt, solvate, or solvate saltthereof. In one embodiment, Form A exhibits high stability. In oneembodiment, Form A is the most thermodynamically stable form.

In one embodiment, Form A of crystalline form of Compound I may compriseof a mixture of one or more forms of polymorphs of Compound I. In someembodiments, the crystalline form of Compound I may comprise ofsubstantially pure form of one polymorph type. In one embodiment, thecrystalline form of Compound I may comprise of over about 99.9%, about99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%,about 99.2%, about 99.1%, or about 99.0% of Form A. In anotherembodiment, the crystalline form of Compound I may comprise over about99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Form A. In someembodiments, the crystalline form of Compound I may comprise over about90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Form A.

In one embodiment, crystalline Form A of Compound I exhibits an XRPDpattern comprising peaks at about 17.48, 20.78, and 21.80 degreestwo-theta with the margin of error of about ±0.5; about ±0.4; about±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In anotherembodiment, the XRPD of the crystalline Form A of Compound I furthercomprises peaks at about 5.19 and 12.94 degrees two-theta with themargin of error of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about±0.1; about ±0.05; or less. In further embodiment, the crystalline FormA of Compound I further comprises at least two peaks selected from about17.80, 18.74, 19.57, 22.59, 25.28, or 29.95 degrees two-theta with themargin of error of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about±0.1; about ±0.05; or less. In further embodiment, the crystalline FormA of Compound I further comprises at least three peaks selected fromabout 17.80, 18.74, 19.57, 22.59, 25.28, or 29.95 degrees two-theta withthe margin of error of about ±0.5; about ±0.4; about ±0.3; about ±0.2;about ±0.1; about ±0.05; or less. In further embodiment, the crystallineForm A of Compound I further comprises at least four peaks selected fromabout 17.80, 18.74, 19.57, 22.59, 25.28, or 29.95 degrees two-theta withthe margin of error of about ±0.5; about ±0.4; about ±0.3; about ±0.2;about ±0.1; about ±0.05; or less. In further embodiment, the crystallineForm A of Compound I further comprises at least five peaks selected fromabout 17.80, 18.74, 19.57, 22.59, 25.28, or 29.95 degrees two-theta withthe margin of error of about ±0.5; about ±0.4; about ±0.3; about ±0.2;about ±0.1; about ±0.05; or less. In further embodiment, the crystallineForm A of Compound I further comprises peaks at about 17.80, 18.74,19.57, 22.59, 25.28, and 29.95 degrees two-theta with the margin oferror of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1;about ±0.05; or less.

In one embodiment, crystalline Form A of Compound I exhibits an XRPDpattern comprising peaks at about 17.48±0.2, 20.78±0.2, and 21.80±0.2degrees two-theta. In one embodiment, crystalline Form A of Compound Iexhibits an XRPD pattern comprising peaks having intensity of at least50% at about 17.48±0.2, 20.78±0.2, and 21.80±0.2 degrees two-theta. Inone embodiment, crystalline Form A of Compound I exhibits an XRPDpattern comprising peaks having intensity of at least 60% at about17.48±0.2, 20.78±0.2, and 21.80±0.2 degrees two-theta. In oneembodiment, crystalline Form A of Compound I exhibits an XRPD patterncomprising peaks having intensity of at least 65% at about 17.48±0.2,20.78±0.2, and 21.80±0.2 degrees two-theta.

In one embodiment, crystalline Form A of Compound I exhibits an XRPDpattern comprising peaks at about 5.19±0.2 and 12.94±0.2 degreestwo-theta. In one embodiment, crystalline Form A of Compound I exhibitsan XRPD pattern comprising peaks having intensity of at least 30% atabout 5.19±0.2 and 12.94±0.2 degrees two-theta. In one embodiment,crystalline Form A of Compound I exhibits an XRPD pattern comprisingpeaks having intensity of at least 35% at about 5.19±0.2 and 12.94±0.2degrees two-theta. In one embodiment, crystalline Form A of Compound Iexhibits an XRPD pattern comprising peaks having intensity of at least40% at about 5.19±0.2 and 12.94±0.2 degrees two-theta. In oneembodiment, crystalline Form A of Compound I exhibits an XRPD patterncomprising peaks having intensity of at least 35% at about 5.19±0.2,12.94±0.2, 17.48±0.2, 20.78±0.2, and 21.80±0.2 degrees two-theta.

In one embodiment, crystalline Form A of Compound I exhibits an XRPDpattern comprising at least two peaks selected from about 17.80±0.2,18.74±0.2, 19.57±0.2, 22.59±0.2, 25.28±0.2, or 29.95±0.2 degreestwo-theta. In one embodiment, crystalline Form A of Compound I exhibitsan XRPD pattern comprising peaks at about 17.80±0.2, 18.74±0.2,19.57±0.2, 22.59±0.2, 25.28±0.2, and 29.95±0.2 degrees two-theta. In oneembodiment, crystalline Form A of Compound I exhibits an XRPD patterncomprising peaks having intensity of at least 15% at about 17.80±0.2,18.74±0.2, 19.57±0.2, 22.59±0.2, 25.28±0.2, and 29.95±0.2 degreestwo-theta. In one embodiment, crystalline Form A of Compound I exhibitsan XRPD pattern comprising peaks having intensity of at least 20% atabout 17.80±0.2, 18.74±0.2, 19.57±0.2, 22.59±0.2, 25.28±0.2, and29.95±0.2 degrees two-theta.

In one embodiment, crystalline Form A of Compound I exhibits an XRPDpattern comprising peaks having intensity of at least 30% at about5.19±0.2, 12.94±0.2, 17.48±0.2, 17.80±0.2, 18.74±0.2, 20.78±0.2, and21.80±0.2 degrees two-theta. In one embodiment, crystalline Form A ofCompound I exhibits an XRPD pattern comprising peaks having intensity ofat least 35% at about 5.19±0.2, 12.94±0.2, 17.48±0.2, 18.74±0.2,20.78±0.2, and 21.80±0.2 degrees two-theta.

In one embodiment, the crystalline Form A of Compound exhibits an XRPDcomprising peaks shown in Table 1A below. In one embodiment, thecrystalline Form A of Compound I exhibits an XRPD comprising peaks shownin Table 1B below.

TABLE 1A XRPD Table of Form A of Compound I °2θ d space (Å) Intensity(%)  5.19 ± 0.20 17.013 ± 0.655  41  9.60 ± 0.20 9.206 ± 0.191 8 10.42 ±0.20 8.483 ± 0.162 6 10.09 ± 0.20 8.118 ± 0.149 12 12.38 ± 0.20 7.144 ±0.115 6 12.94 ± 0.20 6.836 ± 0.105 51 13.17 ± 0.20 6.715 ± 0.101 6 13.52± 0.20 6.544 ± 0.096 15 15.40 ± 0.20 5.749 ± 0.074 13 15.64 ± 0.20 5.661± 0.072 7 15.90 ± 0.20 5.569 ± 0.070 5 16.17 ± 0.20 5.477 ± 0.067 1316.75 ± 0.20 5.289 ± 0.063 7 17.01 ± 0.20 5.208 ± 0.061 8 17.48 ± 0.205.069 ± 0.058 100 17.80 ± 0.20 4.979 ± 0.055 32 18.74 ± 0.28 4.731 ±0.050 38 19.57 ± 0.20 4.532 ± 0.046 23 20.20 ± 0.20 4.392 ± 0.043 920.78 ± 0.20 4.271 ± 0.041 70 21.80 ± 0.20 4.074 ± 0.037 73 22.59 ± 0.203.933 ± 0.034 23 22.99 ± 0.20 3.865 ± 0.033 18 23.29 ± 0.20 3.816 ±0.032 14 23.53 ± 0.20 3.778 ± 0.032 7 24.91 ± 0.20 3.572 ± 0.028 1025.28 ± 0.20 3.520 ± 0.027 23 25.82 ± 0.20 3.448 ± 0.026 5 26.21 ± 0.203.397 ± 0.025 9 26.57 ± 0.20 3.352 ± 0.025 19 27.29 ± 0.20 3.265 ± 0.02312 27.83 ± 0.20 3.203 ± 0.023 14 28.06 ± 0.20 3.177 ± 0.022 13 28.68 ±0.20 3.110 ± 0.021 4 29.09 ± 0.20 3.067 ± 0.021 5 29.59 ± 0.20 3.016 ±0.020 10 29.95 ± 0.20 2.981 ± 0.019 25

TABLE 1B XRPD Table of Form A of Compound I °2θ d space (Å) Intensity(%)  5.19 ± 0.20 17.013 ± 0.655  41 12.94 ± 0.20 6.836 ± 0.105 51 17.48± 0.20 5.069 ± 0.058 100 17.80 ± 0.20 4.979 ± 0.055 32 18.74 ± 0.204.731 ± 0.050 38 19.57 ± 0.20 4.532 ± 0.046 23 20.78 ± 0.20 4.271 ±0.041 70 21.80 ± 0.20 4.074 ± 0.037 73 22.59 ± 0.20 3.933 ± 0.034 2325.28 ± 0.20 3.520 ± 0.027 23 29.95 ± 0.20 2.981 ± 0.019 25

In one specific embodiment, the crystalline Form A of Compound Iexhibits an XRPD pattern that is substantially similar to FIG. 1. In oneembodiment, the XRPD spectrum presented in FIG. 1 contains small amountof NaCl. In one embodiment, the XRPD peaks at 27.3±0.2 and at 31.7±0.2degrees two-theta in FIG. 1 is attributed to the presence of smallamount of NaCl. In one embodiment, the XRPD peaks at 27.3±0.2 degreestwo-theta in Table 1A is attributed to the presence of small amount ofNaCl.

In one embodiment, the crystalline Form A of Compound I exhibits an XRPDpattern that is substantially similar to FIG. 1 provided that peaks at27.3±0.2 and at 31.7±0.2 degrees two-theta are excluded as not beingpart of the characterization of Form A. In one embodiment, thecrystalline Form A of Compound I exhibits an XRPD pattern comprisingpeaks shown in Table 1A, provided that peaks at 27.3±0.2 degreestwo-theta are excluded as not being part of the characterization of FormA.

In one embodiment, the crystalline Form A of Compound I exhibits a TGAthermogram substantially similar to FIG. 2 (top). In one embodiment,crystalline Form A of Compound I shows change in the slope of a TGAthermogram starting at about 284° C. (onset). Without bound to anytheory, this change in the slope of the TGA thermogram is likelyassociated with the decomposition of crystalline Form A of Compound I.

In one embodiment, the crystalline Form A of Compound I exhibits a DSCthermogram comprising an endotherm peak at about 182° C. (onset) withthe error of margin of about ±2.5; about ±2.0; about ±1.5; about ±1.0;about ±0.5; or less. In one embodiment, the crystalline Form A ofCompound I exhibits a DSC thermogram comprising an endotherm peak atabout 185° C. (peak) with the error of margin of about ±2.5; about ±2.0;about ±1.5; about ±1.0; about ±0.5; or less. In one embodiment, thecrystalline Form A of Compound I exhibits a DSC thermogram that issubstantially similar to FIG. 2 (bottom).

In one embodiment, crystalline Form A of Compound I can be obtained as asuitable single crystal. In one embodiment, single crystals of Form Ahas a crystal system that is monoclinic and the space group is P2₁/c. Inone embodiment, the cell parameters and the calculated volume of thesingle crystals of Form A are about: a=17.5550±0.0002 Å,b=10.96169±0.00013 Å, c=13.7961±0.0002 Å, α=90°, β=104.5717±0.0015°,γ=90°, and V=2569.40±0.06 Å³. In one embodiment, single crystals of FormA has a density of about 1.384 g/cm³.

Amorphous Form of Compound I

In one embodiment, the present disclosure relates to solid forms ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof. In one embodiment, the present disclosure relates to anamorphous form of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof. In one embodiment, the presentdisclosure relates to an amorphous form of anhydrous or non-solvatedCompound I or a pharmaceutically acceptable salt thereof. In oneembodiment, the present disclosure relates to an amorphous form ofanhydrous or non-solvated Compound I (not a salt). In one embodiment,the present disclosure relates to an amorphous form of Compound I (not asalt, not a solvate, not a solvate salt).

In another embodiment, the amorphous form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof is ina pharmaceutical composition. In a specific embodiment, thepharmaceutical composition comprises Compound I in a solid dispersion.

In one embodiment, the amorphous form of Compound I exhibits an XRPDpattern that is substantially similar to FIG. 6, third spectrum from thebottom, excluding peaks attributed to the presence of NaCl at about 27and at about 32 degrees two-theta.

In one embodiment, the amorphous form of Compound I exhibits a glasstransition (T_(g)) at about 61° C. with the error of margin of about±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less, as a stepchange in the reversing heat flow signal. In one embodiment, the glasstransition temperature is measured by temperature modulated DSC (TMDSC).In one embodiment, the amorphous form of Compound I exhibits a DSCthermogram comprising an exotherm peak at about 91° C. (peak) with theerror of margin of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about±0.5; or less. In one embodiment, the amorphous form of Compound Iexhibits a DSC thermogram comprising an endotherm peak at about 178° C.(onset) with the error of margin of about ±2.5; about ±2.0; about ±1.5;about ±1.0; about ±0.5; or less. In one embodiment, the amorphous formof Compound I exhibits a DSC thermogram that is substantially similar toFIG. 7.

In one embodiment, the amorphous form of Compound I exhibits a TGAthermogram substantially similar to FIG. 8. In one embodiment, amorphousform of Compound I shows change in the slope of TGA thermogram startingat about 280° C. (onset). Without bound to any theory, this change inthe slope of the TGA thermogram is likely associated with thedecomposition of the amorphous form of Compound I.

In some embodiments, the amorphous form of Compound I exhibits a glasstransition temperature (Tg) in the range of about 60° C. to about 180°C. as measured by differential scanning calorimeter. In someembodiments, the amorphous form of Compound I exhibits a glasstransition temperature (Tg) in the range of about 60° C. to about 90° C.as measured by differential scanning calorimeter. In some embodiments,the amorphous form of Compound I exhibits a glass transition temperature(Tg) in the range of about 70° C. to about 80° C. as measured bydifferential scanning calorimeter. In a specific embodiment, theamorphous form of Compound I is in a pharmaceutical composition, or in amore specific embodiment, a solid dispersion composition.

In some embodiments, the amorphous form of Compound I exhibits an X-raypowder diffraction (XRPD) pattern substantially similar to any one ofthe patterns shown in FIGS. 13 and 15. In a specific embodiment, theamorphous form of Compound I is in a pharmaceutical composition, or in amore specific embodiment, a solid dispersion composition.

In some embodiments, the amorphous form of Compound I exhibits an XRPDpattern substantially similar to a pattern labeled as SDD-A, SDD-B,SDD-C, SDD-D, or SDD-E in FIG. 13 or a pattern labeled as SDD-H, SDD-I,SDD-J, SDD-N, SDD-O, SDD-O, SDD-P, SDD-Q, or SDD-R in FIG. 15. In someembodiments, the amorphous form of Compound I exhibits an XRPD patternsubstantially similar to a pattern labeled as SDD-H, SDD-I, SDD-J,SDD-N, SDD-O, SDD-O, SDD-P, SDD-Q, or SDD-R in FIG. 15. In a specificembodiment, the amorphous form of Compound I is in a pharmaceuticalcomposition, or in a more specific embodiment, a solid dispersioncomposition.

In some embodiments, the amorphous form of Compound I exhibits amodulated differential scanning calorimetry (mDSC) thermogramsubstantially similar to the thermogram labeled as SDD-A, SDD-B, SDD-C,SDD-D, or SDD-E in FIG. 14. In a specific embodiment, the amorphous formof Compound I is in a pharmaceutical composition, or in a more specificembodiment, a solid dispersion composition.

Pharmaceutical Compositions and Formulations

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of acrystalline form of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, as disclosed herein, as the activeingredient, combined with a pharmaceutically acceptable excipient orcarrier. In one embodiment, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a crystalline Form A of Compound I. In one embodiment, the presentinvention provides a pharmaceutical composition comprising atherapeutically effective amount of a crystalline Form A of Compound Iand a pharmaceutically acceptable excipient or carrier. The excipientsare added to the formulation for a variety of purposes.

In one embodiment of the present disclosure, the pharmaceuticalcomposition comprises Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof as a mixture of different forms. In oneembodiment, the pharmaceutical composition comprises crystalline Form Aof Compound I in about 99.9%, about 99.8%, about 99.7%, about 99.6%,about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, orabout 99.0% of the total amount of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof. In one embodiment,the pharmaceutical composition comprises crystalline Form A of CompoundI in about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of thetotal amount of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof. In one embodiment, the pharmaceuticalcomposition comprises crystalline Form A of Compound I in about 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20%of the total amount of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof. In one embodiment, the pharmaceuticalcomposition comprises crystalline Form A of Compound I in about 0.1%,0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%,3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%,11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 18%, or 20% of the total amountof Compound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof.

In one embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of anamorphous form of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, as disclosed herein, as the activeingredient, combined with a pharmaceutically acceptable excipient orcarrier.

In one embodiment, the pharmaceutical composition comprises an amorphousform of Compound I in about 99.9%, about 99.8%, about 99.7%, about99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%,or about 99.0% of the total amount of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof. In one embodiment,the pharmaceutical composition comprises an amorphous form of Compound Iin about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of thetotal amount of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof. In one embodiment, the pharmaceuticalcomposition comprises an amorphous form of Compound I in about 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20% ofthe total amount of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof. In one embodiment, the pharmaceuticalcomposition comprises an amorphous form of Compound I in about 0.1%,0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%,3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%,11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 18%, or 20% of the total amountof Compound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof.

In one embodiment of the present disclosure, the pharmaceuticalcomposition comprises a mixture of a crystalline form and an amorphousform of Compound I or a pharmaceutically acceptable salt, solvate, orsolvate salt thereof. In one embodiment, the mixture comprises anamorphous form of Compound I in about 99%, 98%, 97%, 96%, 95%, 94%, 93%,92%, 91%, or 90% and a crystalline form of Compound I in about 1%, 1.5%,2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%,9%, 9.5%, or 10%, wherein the amount represents the percentage of thetotal amount of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof in the mixture. In one embodiment, themixture comprises an amorphous form of Compound I in about 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20% and acrystalline form of Compound I in about 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%, wherein the amountrepresents the percentage of the total amount of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof inthe mixture. In one embodiment, the mixture comprises a crystalline formof Compound I in about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or90% and an amorphous form of Compound I in about 1%, 1.5%, 2%, 2.5%, 3%,3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or10%, wherein the amount represents the percentage of the total amount ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof in the mixture. In one embodiment, the mixture comprises acrystalline form of Compound I in about 90%, 85%, 80%, 75%, 70%, 65%,60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20% and an amorphous form ofCompound I in about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, or 80%, wherein the amount represents the percentageof the total amount of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof in the mixture. In one embodiment, thecrystalline form of Compound I is Form A.

In one embodiment, the Compound I can be present in the pharmaceuticalcomposition as a pharmaceutically acceptable salt. In one embodiment,the Compound I can be present in the pharmaceutical composition as apharmaceutical solvate. In one embodiment, the Compound I can be presentin the pharmaceutical composition as a pharmaceutical solvate salt. Inone embodiment, the Compound I can be present in the pharmaceuticalcomposition as an amorphous form. In one embodiment, the Compound I canbe present in the pharmaceutical composition as a crystalline form thatis not Form A. In one embodiment, the Compound I can be present in thepharmaceutical composition as a crystalline form that is not Form A thatis anhydrous Compound I. In one embodiment, the Compound I can bepresent in the pharmaceutical composition as a crystalline form that isnot Form A that is anhydrous free base of Compound I.

In one embodiment, a pharmaceutical composition, as described herein,further comprises one or more additional therapeutically active agents.In one embodiment, one or more additional therapeutically active agentsare selected from therapeutics useful for treating cancer, neurologicaldisease, a disorder characterized by abnormal accumulation ofα-synuclein, a disorder of an aging process, cardiovascular disease,bacterial infection, viral infection, mitochondrial related disease,mental retardation, deafness, blindness, diabetes, obesity, autoimmunedisease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoidarthritis. In one embodiment, one or more additional therapeuticallyactive agents are selected from therapeutics useful for treatingprostate cancer of breast cancer.

In some embodiments, the one or more additional therapeutic agents is apoly (ADP-ribose) polymerase (PARP) inhibitor including but not limitedto olaparib, niraparib, rucaparib, talazoparib; an androgen receptorligand-binding domain inhibitor including but not limited toenzalutamide, apalutamide, darolutamide, bicalutamide, nilutamide,flutamide, ODM-204, TAS3681; an inhibitor of CYP17 including but notlimited to galeterone, abiraterone, abiraterone acetate; a microtubuleinhibitor including but not limited to docetaxel, paclitaxel,cabazitaxel (XRP-6258); a modulator of PD-1 or PD-L1 including but notlimited to pembrolizumab, durvalumab, nivolumab, atezolizumab; agonadotropin releasing hormone agonist including but not limited tocyproterone acetate, leuprolide; a 5-alpha reductase inhibitor includingbut not limited to finasteride, dutasteride, turosteride, bexlosteride,izonsteride, FCE 28260, SKF105,111; a vascular endothelial growth factorinhibitor including but not limited to bevacizumab (Avastin); a histonedeacetylase inhibitor including but not limited to OSU-HDAC42; anintegrin alpha-v-beta-3 inhibitor including but not limited to VITAXIN;a receptor tyrosine kinase including but not limited to sunitumib; aphosphoinositide 3-kinase inhibitor including but not limited toalpelisib, buparlisib, idealisib; an anaplastic lymphoma kinase (ALK)inhibitor including but not limited to crizotinib, alectinib; anendothelin receptor A antagonist including but not limited to ZD-4054;an anti-CTLA4 inhibitor including but not limited to MDX-010(ipilimumab); an heat shock protein 27 (HSP27) inhibitor including butnot limited to OGX 427; an androgen receptor degrader including but notlimited to ARV-330, ARV-110; a androgen receptor DNA-binding domaininhibitor including but not limited to VPC-14449; a bromodomain andextra-terminal motif (BET) inhibitor including but not limited toBI-894999, GSK25762, GS-5829; an N-terminal domain inhibitor includingbut not limited to a sintokamide; an alpha-particle emitting radioactivetherapeutic agent including but not limited to radium 233 or a saltthereof; niclosamide; or related compounds thereof; a selective estrogenreceptor modulator (SERM) including but not limited to tamoxifen,raloxifene, toremifene, arzoxifene, bazedoxifene, pipindoxifene,lasofoxifene, enclomiphene; a selective estrogen receptor degrader(SERD) including but not limited to fulvestrant, ZB716, OP-1074,elacestrant, AZD9496, GDC0810, GDC0927, GW5638, GW7604; an aromataseinhibitor including but not limited to anastrazole, exemestane,letrozole; selective progesterone receptor modulators (SPRM) includingbut not limited to mifepristone, lonaprison, onapristone, asoprisnil,lonaprisnil, ulipristal, telapristone; a glucocorticoid receptorinhibitor including but not limited to mifepristone, COR108297,COR125281, ORIC-101, PT150; HER2 receptor antagonist including but notlimited to trastuzumab, neratinib; or a mammalian target of rapamycin(mTOR) inhibitor including but not limited to everolimus, temsirolimus,an AKT inhibitor including but not limited to MK-2206; a Bcl-2 inhibitorincluding but not limited to venetoclax; an aurora kinase inhibitorincluding but not limited to alisertib; a Wnt-targeting antagonistincluding but not limited to DKK-1-4 proteins (Dikhopf), secretedFrazzle related proteins (sFRP); a CYP11a inhibitor including but notlimited to ODM-208; a selective androgen receptor N-terminal domaininhibitor including but not limited to LY2452473; or EZH2 inhibitorincluding but not limited to CPI-1205. In another embodiment, the secondtherapeutically active agent is a nonsteroidal antiandrogen (NSAA).

In one embodiment, pharmaceutical composition comprises a) enzalutamide,apalutamide, or darolutamide, b) a crystalline Form A of Compound I, ora pharmaceutically acceptable salt, solvate, or solvate salt thereof,and c) a pharmaceutically acceptable carrier or excipient. In oneembodiment, pharmaceutical composition comprises a) enzalutamide, b) acrystalline Form A of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, and c) a pharmaceutically acceptablecarrier or excipient.

In one embodiment, pharmaceutical composition comprises a) enzalutamide,apalutamide, or darolutamide, b) an amorphous form of Compound I, or apharmaceutically acceptable salt, solvate, or solvate salt thereof, andc) a pharmaceutically acceptable carrier or excipient. In oneembodiment, pharmaceutical composition comprises a) enzalutamide, b) anamorphous form of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, and c) a pharmaceutically acceptablecarrier or excipient.

In one embodiment, pharmaceutical composition comprises venetoclax, acrystalline Form A of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, and a pharmaceutically acceptablecarrier or excipient.

In one embodiment, pharmaceutical composition comprises venetoclax, anamorphous form of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, and a pharmaceutically acceptablecarrier or excipient.

In a further embodiment of the present disclosure, a pharmaceuticalcomposition comprising one or more solid forms of Compound I (e.g., acrystalline form such as Form A or an amorphous form), or apharmaceutically acceptable salt, solvate, or solvate salt thereof, anda pharmaceutically acceptable excipient or adjuvant is provided. Thepharmaceutically acceptable excipients and adjuvants are added to thecomposition or formulation for a variety of purposes. In anotherembodiment, a pharmaceutical composition comprising one or more solidforms of Compound I, or a pharmaceutically acceptable salt, solvate, orsolvate salt thereof, further comprises a pharmaceutically acceptablecarrier. In one embodiment, a pharmaceutically acceptable carrierincludes a pharmaceutically acceptable excipient, binder, and/ordiluent. In one embodiment, suitable pharmaceutically acceptableexcipients include, but are not limited to, water, salt solutions,alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesiumstearate, talc, silicic acid, viscous paraffin, hydroxymethylcelluloseand polyvinylpyrrolidone.

In certain embodiments, the pharmaceutical compositions of the presentdisclosure may additionally contain other adjunct componentsconventionally found in pharmaceutical compositions, at theirart-established usage levels. Thus, for example, the pharmaceuticalcompositions may contain additional, compatible, pharmaceutically-activematerials such as, for example, antipruritics, astringents, localanesthetics or anti-inflammatory agents, or may contain additionalmaterials useful in physically formulating various dosage forms of thecompositions of the present invention, such as dyes, flavoring agents,preservatives, antioxidants, opacifiers, thickening agents andstabilizers. However, such materials, when added, should not undulyinterfere with the biological activities of the components of thecompositions of the present invention. The formulations can besterilized and, if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringsand/or aromatic substances and the like which do not deleteriouslyinteract with the oligonucleotide(s) of the formulation.

For the purposes of this disclosure, the solid forms of Compound I ofthe present disclosure can be formulated for administration by a varietyof means including orally, parenterally, by inhalation spray, topically,or rectally in formulations containing pharmaceutically acceptablecarriers, adjuvants and vehicles. The term parenteral as used hereincludes subcutaneous, intravenous, intramuscular, and intraarterialinjections with a variety of infusion techniques. Intraarterial andintravenous injection as used herein includes administration throughcatheters.

The solid forms of Compound I disclosed herein can be formulated inaccordance with the routine procedures adapted for desiredadministration route. Accordingly, the solid forms of Compound Idisclosed herein can take such forms as suspensions, solutions oremulsions in oily or aqueous vehicles, and can contain formulatoryagents such as suspending, stabilizing and/or dispersing agents. Thesolid forms of Compound I disclosed herein can also be formulated as apreparation for implantation or injection. Thus, for example, the solidforms of Compound I can be formulated with suitable polymeric orhydrophobic materials (e.g., as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives (e.g., as asparingly soluble salt). Alternatively, the active ingredient can be inpowder form for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use. Suitable formulations for each of thesemethods of administration can be found, for example, in Remington: TheScience and Practice of Pharmacy, A. Gennaro, ed., 20th edition,Lippincott, Williams & Wilkins, Philadelphia, Pa.

In certain embodiments, a pharmaceutical composition of the presentdisclosure is prepared using known techniques, including, but notlimited to mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or tableting processes.

In one embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a compound of formula (I)-(VI) and/or (A)-(H-I),or a pharmaceutically acceptable salt, solvate, or solvate salt thereof,as disclosed herein, combined with a pharmaceutically acceptablecarrier. In one embodiment, suitable pharmaceutically acceptablecarriers include, but are not limited to, inert solid fillers ordiluents and sterile aqueous or organic solutions. Pharmaceuticallyacceptable carriers are well known to those skilled in the art andinclude, but are not limited to, from about 0.01 to about 0.1 M andpreferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceuticallyacceptable carriers can be aqueous or non-aqueous solutions, suspensionsand emulsions. Examples of non-aqueous solvents suitable for use in thepresent application include, but are not limited to, propylene glycol,polyethylene glycol, vegetable oils such as olive oil, and injectableorganic esters such as ethyl oleate.

Aqueous carriers suitable for use in the present application include,but are not limited to, water, ethanol, alcoholic/aqueous solutions,glycerol, emulsions or suspensions, including saline and buffered media.Oral carriers can be elixirs, syrups, capsules, tablets and the like.

Liquid carriers suitable for use in the present application can be usedin preparing solutions, suspensions, emulsions, syrups, elixirs andpressurized compounds. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable liquid carrier such as water,an organic solvent, a mixture of both or pharmaceutically acceptableoils or fats. The liquid carrier can contain other suitablepharmaceutical additives such as solubilizers, emulsifiers, buffers,preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, colors, viscosity regulators, stabilizers orosmo-regulators.

Liquid carriers suitable for use in the present application include, butare not limited to, water (partially containing additives as above, e.g.cellulose derivatives, preferably sodium carboxymethyl cellulosesolution), alcohols (including monohydric alcohols and polyhydricalcohols, e.g. glycols) and their derivatives, and oils (e.g.fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also include an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form comprising solid forms of Compound I for parenteraladministration. The liquid carrier for pressurized compounds disclosedherein can be halogenated hydrocarbon or other pharmaceuticallyacceptable propellent.

Solid carriers suitable for use in the present application include, butare not limited to, inert substances such as lactose, starch, glucose,methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol andthe like. A solid carrier can further include one or more substancesacting as flavoring agents, lubricants, solubilizers, suspending agents,fillers, glidants, compression aids, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders, thecarrier can be a finely divided solid which is in admixture with thefinely divided active compound. In tablets, the active compound is mixedwith a carrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active compound. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins. Atablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with abinder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose) surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropyl methylcellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach.

Parenteral carriers suitable for use in the present application include,but are not limited to, sodium chloride solution, Ringer's dextrose,dextrose and sodium chloride, lactated Ringer's and fixed oils.Intravenous carriers include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose andthe like. Preservatives and other additives can also be present, suchas, for example, antimicrobials, antioxidants, chelating agents, inertgases and the like.

Carriers suitable for use in the present application can be mixed asneeded with disintegrants, diluents, granulating agents, lubricants,binders and the like using conventional techniques known in the art. Thecarriers can also be sterilized using methods that do not deleteriouslyreact with the compounds, as is generally known in the art.

Diluents may be added to the formulations of the present invention.Diluents increase the bulk of a solid pharmaceutical composition and/orcombination and may make a pharmaceutical dosage form containing thecomposition and/or combination easier for the patient and care giver tohandle. Diluents for solid compositions and/or combinations include, forexample, microcrystalline cellulose (e.g., AVICEL), microtine cellulose,lactose, starch, pregelatinized starch, calcium carbonate, calciumsulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphatedihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate,magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.,EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride,sorbitol, and talc.

Additional embodiments relate to the pharmaceutical formulations whereinthe formulation is selected from the group consisting of a solid,powder, liquid and a gel. In certain embodiments, a pharmaceuticalcomposition of the present invention is a solid (e.g., a powder, tablet,a capsule, granulates, and/or aggregates). In certain of suchembodiments, a solid pharmaceutical composition comprising one or moreingredients known in the art, including, but not limited to, starches,sugars, diluents, granulating agents, lubricants, binders, anddisintegrating agents.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions and/orcombinations include acacia, alginic acid, carbomer (e.g., carbopol),carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guargum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose,hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose(e.g., METHOCEL), liquid glucose, magnesium aluminum silicate,maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.,KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition and/or combination. Disintegrants include alginicacid, carboxymethylcellulose calcium, carboxymethylcellulose sodium(e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide,croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE),guar gum, magnesium aluminum silicate, methyl cellulose,microcrystalline cellulose, polacrilin potassium, powdered cellulose,pregelatinized starch, sodium alginate, sodium starch glycolate (e.g.,EXPLOTAB), potato starch, and starch.

Glidants can be added to improve the flowability of anon-compacted solidcomposition and/or combination and to improve the accuracy of dosing.Excipients that may function as glidants include colloidal silicondioxide, magnesium trisilicate, powdered cellulose, starch, talc, andtribasic calcium phosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition and/or combination to reduce adhesion and easethe release of the product from the dye. Lubricants include magnesiumstearate, calcium stearate, glyceryl monostearate, glycerylpalmitostearate, hydrogenated castor oil, hydrogenated vegetable oil,mineral oil, polyethylene glycol, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the compositionand/or combination of the present invention include maltol, vanillin,ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, andtartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In certain embodiments, a pharmaceutical composition of the presentinvention is a liquid (e.g., a suspension, elixir and/or solution). Incertain of such embodiments, a liquid pharmaceutical composition isprepared using ingredients known in the art, including, but not limitedto, water, glycols, oils, alcohols, flavoring agents, preservatives, andcoloring agents.

Liquid pharmaceutical compositions can be prepared using one or moresolid forms of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, and any other solid excipients wherethe components are dissolved or suspended in a liquid carrier such aswater, vegetable oil, alcohol, polyethylene glycol, propylene glycol, orglycerin.

For example, formulations for parenteral administration can contain ascommon excipients sterile water or saline, polyalkylene glycols such aspolyethylene glycol, oils of vegetable origin, hydrogenated naphthalenesand the like. In particular, biocompatible, biodegradable lactidepolymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers can be useful excipients tocontrol the release of active compounds. Other potentially usefulparenteral delivery systems include ethylene-vinyl acetate copolymerparticles, osmotic pumps, implantable infusion systems, and liposomes.Formulations for inhalation administration contain as excipients, forexample, lactose, or can be aqueous solutions containing, for example,polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for parenteral administration canalso include glycocholate for buccal administration, methoxysalicylatefor rectal administration, or citric acid for vaginal administration.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition and/or combination anactive ingredient or other excipient that is not soluble in the liquidcarrier. Emulsifying agents that may be useful in liquid compositionsand/or combinations of the present invention include, for example,gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus,pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetylalcohol.

Liquid pharmaceutical compositions can also contain a viscosityenhancing agent to improve the mouth-feel of the product and/or coat thelining of the gastrointestinal tract. Such agents include acacia,alginic acid bentonite, carbomer, carboxymethylcellulose calcium orsodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatinguar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylenecarbonate, propylene glycol alginate, sodium alginate, sodium starchglycolate, starch tragacanth, and xanthan gum.

Sweetening agents such as aspartame, lactose, sorbitol, saccharin,sodium saccharin, sucrose, aspartame, fructose, mannitol, and invertsugar may be added to improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxyl toluene, butylated hydroxyanisole, andethylenediamine tetraacetic acid may be added at levels safe foringestion to improve storage stability.

A liquid composition can also contain a buffer such as guconic acid,lactic acid, citric acid or acetic acid, sodium guconate, sodiumlactate, sodium citrate, or sodium acetate. Selection of excipients andthe amounts used may be readily determined by the formulation scientistbased upon experience and consideration of standard procedures andreference works in the field.

In one embodiment, a pharmaceutical composition is prepared foradministration by injection (e.g., intravenous, subcutaneous,intramuscular, etc.). In certain of such embodiments, a pharmaceuticalcomposition comprises a carrier and is formulated in aqueous solution,such as water or physiologically compatible buffers such as Hanks'ssolution, Ringer's solution, or physiological saline buffer. In certainembodiments, other ingredients are included (e.g., ingredients that aidin solubility or serve as preservatives). In certain embodiments,injectable suspensions are prepared using appropriate liquid carriers,suspending agents and the like. Certain pharmaceutical compositions forinjection are presented in unit dosage form, e.g., in ampoules or inmulti-dose containers. Certain pharmaceutical compositions for injectionare suspensions, solutions or emulsions in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Certain solvents suitable for use in pharmaceuticalcompositions for injection include, but are not limited to, lipophilicsolvents and fatty oils, such as sesame oil, synthetic fatty acidesters, such as ethyl oleate or triglycerides, and liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, such suspensions may also contain suitablestabilizers or agents that increase the solubility of the pharmaceuticalagents to allow for the preparation of highly concentrated solutions.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such as a solution in 1,3-butane-diol or prepared as alyophilized powder. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile fixed oils may conventionally be employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid may likewise be used in the preparationof injectables. Formulations for intravenous administration can comprisesolutions in sterile isotonic aqueous buffer. Where necessary, theformulations can also include a solubilizing agent and a localanesthetic to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampule orsachet indicating the quantity of active agent. Where the solid form ofCompound I is to be administered by infusion, it can be dispensed in aformulation with an infusion bottle containing sterile pharmaceuticalgrade water, saline or dextrose/water. Where the solid form of CompoundI is administered by injection, an ampule of sterile water for injectionor saline can be provided so that the ingredients can be mixed prior toadministration.

Suitable formulations further include aqueous and non-aqueous sterileinjection solutions that can contain antioxidants, buffers,bacteriostats, bactericidal antibiotics and solutes that render theformulation isotonic with the bodily fluids of the intended recipient;and aqueous and non-aqueous sterile suspensions, which can includesuspending agents and thickening agents.

In certain embodiments, a pharmaceutical composition of the presentinvention is formulated as a depot preparation. Certain such depotpreparations are typically longer acting than non-depot preparations. Incertain embodiments, such preparations are administered by implantation(for example subcutaneously or intramuscularly) or by intramuscularinjection. In certain embodiments, depot preparations are prepared usingsuitable polymeric or hydrophobic materials (for example an emulsion inan acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

In certain embodiments, a pharmaceutical composition of the presentinvention comprises a delivery system. Examples of delivery systemsinclude, but are not limited to, liposomes and emulsions. Certaindelivery systems are useful for preparing certain pharmaceuticalcompositions including those comprising hydrophobic compounds. Incertain embodiments, certain organic solvents such as dimethylsulfoxideare used.

In certain embodiments, a pharmaceutical composition of the presentinvention comprises a co-solvent system. Certain of such co-solventsystems comprise, for example, benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. In certainembodiments, such co-solvent systems are used for hydrophobic compounds.A non-limiting example of such a co-solvent system is the VPD co-solventsystem, which is a solution of absolute ethanol comprising 3% w/v benzylalcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/vpolyethylene glycol 300. The proportions of such co-solvent systems maybe varied considerably without significantly altering their solubilityand toxicity characteristics. Furthermore, the identity of co-solventcomponents may be varied: for example, other surfactants may be usedinstead of Polysorbate 80; the fraction size of polyethylene glycol maybe varied; other biocompatible polymers may replace polyethylene glycol,e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides maysubstitute for dextrose.

In certain embodiments, a pharmaceutical composition of the presentinvention comprises a sustained-release system. A non-limiting exampleof such a sustained-release system is a semi-permeable matrix of solidhydrophobic polymers. In certain embodiments, sustained-release systemsmay, depending on their chemical nature, release pharmaceutical agentsover a period of hours, days, weeks or months.

Appropriate pharmaceutical compositions of the present disclosure can bedetermined according to any clinically-acceptable route ofadministration of the composition to the subject. The manner in whichthe composition is administered is dependent, in part, upon the causeand/or location. One skilled in the art will recognize the advantages ofcertain routes of administration. The method includes administering aneffective amount of the therapeutically active agent or one or moresolid forms of Compound I (or composition comprising the therapeuticagent or Compound I) to achieve a desired biological response, e.g., anamount effective to alleviate, ameliorate, or prevent, in whole or inpart, a symptom of a condition to be treated, e.g., oncology andneurology disorders. In various aspects, the route of administration issystemic, e.g., oral or by injection. The therapeutic agents or CompoundI, or pharmaceutically acceptable salts or derivatives thereof, areadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperintoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecally,intraportally, and parenterally. Alternatively or in addition, the routeof administration is local, e.g., topical, intra-tumor and peri-tumor.In some embodiments, the solid form of Compound I is administeredorally.

In certain embodiments, a pharmaceutical composition of the presentdisclosure is prepared for oral administration. In certain of suchembodiments, a pharmaceutical composition is formulated by combining oneor more agents and pharmaceutically acceptable carriers. Certain of suchcarriers enable pharmaceutical compositions to be formulated as tablets,pills, dragees, capsules, liquids, gels, syrups, slurries, suspensionsand the like, for oral ingestion by a subject. Suitable excipientsinclude, but are not limited to, fillers, such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). In certain embodiments, such a mixture isoptionally ground and auxiliaries are optionally added. In certainembodiments, pharmaceutical compositions are formed to obtain tablets ordragee cores. In certain embodiments, disintegrating agents (e.g.,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate) are added.

In certain embodiments, dragee cores are provided with coatings. Incertain such embodiments, concentrated sugar solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquersolutions, and suitable organic solvents or solvent mixtures. Dyestuffsor pigments may be added to tablets or dragee coatings.

In certain embodiments, pharmaceutical compositions for oraladministration are push-fit capsules made of gelatin. Certain of suchpush-fit capsules comprise one or more pharmaceutical agents of thepresent invention in admixture with one or more filler such as lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In certain embodiments,pharmaceutical compositions for oral administration are soft, sealedcapsules made of gelatin and a plasticizer, such as glycerol orsorbitol. In certain soft capsules, one or more pharmaceutical agents ofthe present invention are be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added.

In certain embodiments, pharmaceutical compositions are prepared forbuccal administration. Certain of such pharmaceutical compositions aretablets or lozenges formulated in conventional manner.

In certain embodiments, a pharmaceutical composition is prepared fortransmucosal administration. In certain of such embodiments, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

In certain embodiments, a pharmaceutical composition is prepared foradministration by inhalation. Certain of such pharmaceuticalcompositions for inhalation are prepared in the form of an aerosol sprayin a pressurized pack or a nebulizer. Certain of such pharmaceuticalcompositions comprise a propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In certain embodiments using a pressurized aerosol,the dosage unit may be determined with a valve that delivers a meteredamount. In certain embodiments, capsules and cartridges for use in aninhaler or insufflator may be formulated. Certain of such formulationscomprise a powder mixture of a pharmaceutical agent of the invention anda suitable powder base such as lactose or starch.

In other embodiments the solid forms of Compound I of the presentdisclosure are administered by the intravenous route. In furtherembodiments, the parenteral administration may be provided in a bolus orby infusion.

In certain embodiments, a pharmaceutical composition is prepared forrectal administration, such as a suppository or retention enema. Certainof such pharmaceutical compositions comprise known ingredients, such ascocoa butter and/or other glycerides.

In certain embodiments, a pharmaceutical composition is prepared fortopical administration. Certain of such pharmaceutical compositionscomprise bland moisturizing bases, such as ointments or creams.Exemplary suitable ointment bases include, but are not limited to,petrolatum, petrolatum plus volatile silicones, and lanolin and water inoil emulsions. Exemplary suitable cream bases include, but are notlimited to, cold cream and hydrophilic ointment.

In certain embodiments, the therapeutically effective amount issufficient to prevent, alleviate or ameliorate symptoms of a disease orto prolong the survival of the subject being treated. Determination of atherapeutically effective amount is well within the capability of thoseskilled in the art.

In certain embodiments, one or more solid forms of Compound I, or apharmaceutically acceptable salt, solvate, or solvate salt thereof, areformulated as a prodrug. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically more active form. In certainembodiments, prodrugs are useful because they are easier to administerthan the corresponding active form. For example, in certain instances, aprodrug may be more bioavailable (e.g., through oral administration)than is the corresponding active form. In certain instances, a prodrugmay have improved solubility compared to the corresponding active form.In certain embodiments, prodrugs are less water soluble than thecorresponding active form. In certain instances, such prodrugs possesssuperior transmittal across cell membranes, where water solubility isdetrimental to mobility. In certain embodiments, a prodrug is an ester.In certain such embodiments, the ester is metabolically hydrolyzed tocarboxylic acid upon administration. In certain instances the carboxylicacid containing a solid form of Compound I is the corresponding activeform. In certain embodiments, a prodrug comprises a short peptide(polyaminoacid) bound to an acid group. In certain of such embodiments,the peptide is cleaved upon administration to form the correspondingactive form.

In certain embodiments, a prodrug is produced by modifying apharmaceutically active compound such that the Compound I will beregenerated upon in vivo administration. The prodrug can be designed toalter the metabolic stability or the transport characteristics of adrug, to mask side effects or toxicity, to improve the flavor of a drugor to alter other characteristics or properties of a drug. By virtue ofknowledge of pharmacodynamic processes and drug metabolism in vivo,those of skill in this art, once a pharmaceutically active compound isknown, can design prodrugs of the compound (see, e.g., Nogrady (1985)Medicinal Chemistry A Biochemical Approach, Oxford University Press, NewYork, pages 388-392).

In various aspects, the amount of the one or more solid forms ofCompound I, or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof can be administered at about 0.001 mg/kg to about 100 mg/kgbody weight (e.g., about 0.01 mg/kg to about 10 mg/kg or about 0.1 mg/kgto about 5 mg/kg).

The concentration of a disclosed solid forms of Compound I in apharmaceutically acceptable mixture will vary depending on severalfactors, including the dosage of the solid forms of Compound I to beadministered, the pharmacokinetic characteristics of the solid form(s)employed, and the route of administration. The agent may be administeredin a single dose or in repeat doses. The dosage regimen utilizing thesolid forms of Compound I of the present invention is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient; and the particular solid forms or saltthereof employed. Treatments may be administered daily or morefrequently depending upon a number of factors, including the overallhealth of a patient, and the formulation and route of administration ofthe selected form(s). An ordinarily skilled physician or veterinariancan readily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

The solid forms of Compound I, or a pharmaceutically acceptable salt,solvate, or solvate salt thereof, or pharmaceutical compositions of thepresent disclosure may be manufactured and/or administered in single ormultiple unit dose forms.

Therapeutic Use

The crystalline forms and the pharmaceutical compositions of the presentdisclosure find use in any number of methods. For example, in someembodiments the crystalline forms and the pharmaceutical compositionsare useful in methods for modulating androgen receptor (AR). In someembodiments, modulating androgen receptor (AR) activity is in amammalian cell. In some embodiments, modulating androgen receptor (AR)can be in a subject in need thereof (e.g., a mammalian subject) and fortreatment of any of the described conditions or diseases.

In one embodiment, the modulating AR is binding to AR. In otherembodiments, the modulating AR is inhibiting AR.

In one embodiment, the modulating AR is modulating AR N-terminal domain(NTD).

In one embodiment, the modulating AR is binding to AR NTD. In otherembodiments, the modulating AR is inhibiting AR NTD. In one embodiment,the modulating AR is modulating AR N-terminal domain (NTD). In someembodiments, modulating the AR is inhibiting transactivation of androgenreceptor N-terminal domain (NTD).

In other embodiments, modulating androgen receptor (AR) activity is fortreatment of at least one indication selected from the group consistingof: prostate cancer, breast cancer, ovarian cancer, bladder cancer,pancreatic cancer, hepatocellular cancer, endometrial cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy,age related macular degeneration, and combinations thereof. For example,in some embodiments, the indication is prostate cancer. In otherembodiments, the prostate cancer is primary/localized prostate cancer,locally advanced prostate cancer, recurrent prostate cancer, metastaticprostate cancer, advanced prostate cancer, or metastaticcastration-resistant prostate cancer (CRPC), or hormone-sensitiveprostate cancer. While in other embodiments, the prostate cancer isandrogen dependent prostate cancer. In other embodiments, the spinal andbulbar muscular atrophy is Kennedy's disease.

In one embodiment of the present disclosure, a method of treating acondition associated with cell proliferation in a patient in needthereof is provided. In one embodiment, the present invention provides amethod of treating cancer or tumors. In another embodiment, the presentinvention provides a method of treating prostate cancer or breastcancer. In another embodiment, the present invention provides a methodof treating prostate cancer.

In one embodiment of the present disclosure, a method of reducing,inhibiting, or ameliorating cell proliferation in a patient in needthereof is provided. In one embodiment, the reducing, inhibiting, orameliorating in the method disclosed herein, is in vivo. In anotherembodiment, the reducing, inhibiting, or ameliorating is in vitro.

In one embodiment, the cells in the method disclosed herein, are acancer cells. In one embodiment, the cancer cells are a prostate cancercells. In one embodiment, the prostate cancer cells are cells ofprimary/localized prostate cancer (newly diagnosed or early stage),locally advanced prostate cancer, recurrent prostate cancer (e.g.,prostate cancer which was not cured with primary therapy), metastaticprostate cancer, advanced prostate cancer (e.g., after castration forrecurrent prostate cancer), metastatic castration-resistant prostatecancer (CRPC), or hormone-sensitive prostate cancer. In anotherembodiment, the prostate cancer cells are cells of a metastaticcastration-resistant prostate cancer. In other embodiments, the prostatecancer cells are an androgen-dependent prostate cancer cells or anandrogen-independent prostate cancer cells. In one embodiment, thecancer cells are breast cancer cells.

In one embodiment, the condition or disease associated with cellproliferation is cancer. In one embodiment of any one of the methodsdisclosed herein, the cancer is selected from the group consisting of:prostate cancer, breast cancer, ovarian cancer, endometrial cancer,salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy, and age-related macular degeneration. In one embodiment, thecondition or disease is prostate cancer. In one embodiment, prostatecancer is selected from primary/localized prostate cancer, locallyadvanced prostate cancer, recurrent prostate cancer, metastatic prostatecancer, advanced prostate cancer, metastatic castration-resistantprostate cancer (CRPC), or hormone-sensitive prostate cancer. In anotherembodiment, the prostate cancer is a metastatic castration-resistantprostate cancer. In some embodiments, the prostate cancer is anandrogen-dependent prostate cancer cells or an androgen-independentprostate cancer. In one embodiment, the condition or disease is breastcancer. In one embodiment, the breast cancer is AR-positive triplenegative breast cancer.

In another embodiment of the present disclosure, a method for reducingor preventing tumor growth, comprising contacting tumor cells with apharmaceutical composition or a combination as disclosed herein.

In one embodiment, reducing or preventing tumor growth includesreduction in tumor volume. In one embodiment, reducing or preventingtumor growth includes complete elimination of tumors. In one embodiment,reducing or preventing tumor growth includes stopping or halting theexisting tumor to grow. In one embodiment, reducing or preventing tumorgrowth includes reduction in the rate of tumor growth. In oneembodiment, reducing or preventing tumor growth includes reduction inthe rate of tumor growth such that the rate of tumor growth beforetreating a patient with the methods disclosed herein (0) is faster thanthe rate of tumor growth after said treatment (r2) such that r1>r2.

In one embodiment, the reducing or preventing in the method disclosedherein is in vivo. In another embodiment, the treating is in vitro.

In one embodiment, the tumor cell in the method disclosed herein isselected from prostate cancer, breast cancer, ovarian cancer,endometrial cancer, or salivary gland carcinoma. In one embodiment, thetumor cells are prostate cancer tumor cells. In one embodiment, theprostate cancer tumor cells are tumor cells of primary/localizedprostate cancer, locally advanced prostate cancer, recurrent prostatecancer, metastatic prostate cancer, advanced prostate cancer, metastaticcastration-resistant prostate cancer (CRPC), or hormone-sensitiveprostate cancer. In other embodiments, the prostate cancer is ametastatic castration-resistant prostate cancer. In some embodiments,the prostate cancer is androgen-dependent prostate cancer orandrogen-independent prostate cancer. In another embodiment, the tumorcells are is breast cancer tumor cells.

Therapeutic Use Related to Androgen Receptor Driven Gene Expression

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerbefore and/or after treatment of the subject with a solid form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof.

In one embodiment of the present disclosure, a method of treating apatient with abnormal androgen receptor driven gene activity with asolid form of Compound I or a pharmaceutically acceptable salt, solvate,or solvate salt thereof, alone or in combination with a secondtherapeutic agent is provided.

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerbefore treatment with a solid form of Compound I, and determining in thesample, the expression level of an androgen receptor driven genes. Inanother specific embodiment, after testing the expression level ofandrogen receptor driven genes, the subject is administered a solid formof Compound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof, alone and or in combination with a second therapeuticallyactive agent as disclosed herein. In a specific embodiment, the genesare one or more selected from the group consisting of KLK2, FKBP5,TMPRSS2, KLK3, NCAPD3, NKX3-1, NDRG1, STEAP4, FAM105A, AKAP12, PMEPA1,PLPP1, SNA12, ACSL3, ERRFl1, CDC6, ELL2, CENPN, RHOU, EAF2, SGK1,SLC16A6, TIPARP, IGF1R, CCND1, ADAMTS1, and PRR15L.

In one embodiment, the present disclosure provides a method of treatingcancer in a subject having abnormal gene expression of one or moreandrogen receptor driven genes, comprising administering to the subjecta solid form of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof. In one embodiment of any one of themethods disclosed herein, the androgen receptor driven gene is anandrogen receptor full-length driven gene. In one embodiment, theandrogen receptor driven gene is an androgen receptor V7 driven gene. Inone embodiment of any one of the methods disclosed herein, the gene withan abnormal activity is selected from KLK2, FKBP5, TMPRSS2, KLK3,NCAPD3, NKX3-1, NDRG1, STEAP4, FAM105A, AKAP12, PMEPA1, PLPP1, SNA12,ACSL3, ERRFl1, CDC6, ELL2, CENPN, RHOU, EAF2, SGK1, SLC16A6, TIPARP,IGF1R, CCND1, ADAMTS1, or PRR15L. In one embodiment of the methodsdisclosed herein, cancer is selected from prostate cancer, breastcancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.In one embodiment, the cancer is prostate cancer. In one embodiment, theprostate cancer is selected from primary/localized prostate cancer,locally advanced prostate cancer, recurrent prostate cancer, metastaticprostate cancer, advanced prostate cancer, metastaticcastration-resistant prostate cancer (CRPC), or hormone-sensitiveprostate cancer. In other embodiments, the prostate cancer is ametastatic castration-resistant prostate cancer. In some embodiments,the prostate cancer is androgen-dependent prostate cancer orandrogen-independent prostate cancer. In another embodiment, the canceris breast cancer. In a specific embodiment, the solid form of Compound Iis crystalline Form A. In a specific embodiment, the solid form ofCompound I is an amorphous form.

In one embodiment, the present disclosure provides a method of treatingcancer in a subject having abnormal gene expression of one or moreandrogen receptor driven genes, comprising administering to the subjecta solid form of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof. In one embodiment, the solid form ofCompound I is crystalline Form A or an amorphous form in combinationwith a second therapeutically active agent as disclosed herein. In aspecific embodiment, the second therapeutically active agent is anonsteroidal antiandrogen (NSAA). In one embodiment of thepharmaceutical composition of the present disclosure, the androgenreceptor ligand-binding domain inhibitor is enzalutamide, apalutamide,darolutamide, bicalutamide, nilutamide, flutamide, ODM-204, or TAS3681.In one embodiment, the androgen receptor ligand-binding domain inhibitoris enzalutamide.

In one embodiment of any one of the methods disclosed herein, theandrogen receptor driven gene is an androgen receptor full-length drivengene. In one embodiment, the androgen receptor driven gene is anandrogen receptor V7 driven gene. In one embodiment of any one of themethods disclosed herein, the gene with an abnormal activity is selectedfrom KLK2, FKBP5, TMPRSS2, KLK3, NCAPD3, NKX3-1, NDRG1, STEAP4, FAM105A,AKAP12, PMEPA1, PLPP1, SNA12, ACSL3, ERRFl1, CDC6, ELL2, CENPN, RHOU,EAF2, SGK1, SLC16A6, TIPARP, IGF1R, CCND1, ADAMTS1, or PRR15L. In oneembodiment of the methods disclosed herein, cancer is selected fromprostate cancer, breast cancer, ovarian cancer, endometrial cancer, orsalivary gland carcinoma. In one embodiment, the cancer is prostatecancer. In one embodiment, the prostate cancer is selected fromprimary/localized prostate cancer, locally advanced prostate cancer,recurrent prostate cancer, metastatic prostate cancer, advanced prostatecancer, metastatic castration-resistant prostate cancer (CRPC), orhormone-sensitive prostate cancer. In other embodiments, the prostatecancer is a metastatic castration-resistant prostate cancer. In someembodiments, the prostate cancer is androgen-dependent prostate canceror androgen-independent prostate cancer. In another embodiment, thecancer is breast cancer. In a specific embodiment, the solid form ofCompound I is crystalline Form A and the second therapeutically activeagent is enzalutamide. In a specific embodiment, the solid form ofCompound I is an amorphous form and the second therapeutically activeagent is enzalutamide.

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerafter treatment with an androgen receptor modulator, and determining, inthe sample, the expression level of an androgen receptor driven gene,where if the gene expression level, when compared to a referencestandard level, is decreased before or after treatment with the androgenreceptor modulator, then proceeding with or resuming treatment of thesubject with a therapeutically effective amount of the androgen receptormodulator and/or a second therapeuticall active agent. In a specificembodiment, the gene is selected from one or more of the groupconsisting of KLK2, FKBP5, TMPRSS2, KLK3, NCAPD3, NKX3-1, NDRG1, STEAP4,FAM105A, AKAP12, PMEPA1, PLPP1, SNA12, ACSL3, ERRFl1, CDC6, ELL2, CENPN,RHOU, EAF2, SGK1, SLC16A6, TIPARP, IGF1R, CCND1, ADAMTS1, and PRR15L. Inone embodiment, an androgen receptor modulator administered before thesample of cancer is obtained can be the same or different from anandrogen receptor modulator administered after the androgen receptordriven gene expression levels are assessed. In one embodiment, theandrogen receptor modulator is a solid form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof.

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerafter treatment with an androgen receptor modulator, and determining, inthe sample, the expression level of an androgen receptor driven gene,where if the gene expression level, when compared to a referencestandard level, is decreased before or after treatment with the androgenreceptor modulator, then proceeding with or resuming treatment of thesubject with a therapeutically effective amount of the androgen receptormodulator or a different androgen receptor modulator and a secondtherapeutic agent, wherein the gene is selected from one or more of thegroup consisting of KLK2, FKBP5, TMPRSS2, KLK3, NCAPD3, NKX3-1, NDRG1,STEAP4, FAM105A, AKAP12, PMEPA1, PLPP1, SNA12, ACSL3, ERRFl1, CDC6,ELL2, CENPN, RHOU, EAF2, SGK1, SLC16A6, TIPARP, IGF1R, CCND1, ADAMTS1,and PRR15L. In one embodiment, the second therapeutic agent is anandrogen receptor ligand-binding domain inhibitor is enzalutamide,apalutamide, darolutamide, bicalutamide, nilutamide, flutamide, ODM-204,or TAS3681. In one embodiment, the androgen receptor ligand-bindingdomain inhibitor is enzalutamide. In one embodiment, the secondtherapeutic agent is a Bcl-2 inhibitor. In one embodiment, the Bcl-2inhibitor is venetoclax. In one embodiment, the second therapeutic agentis an androgen receptor N-terminal domain inhibitor. In one embodiment,the androgen receptor modulator is a solid form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof.

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerafter treatment with an androgen receptor modulator, and determining, inthe sample, the expression level of an androgen receptor driven genes,where if the gene expression level, when compared to a referencestandard level, is decreased before or after treatment with the androgenreceptor modulator, then proceeding with or resuming treatment of thesubject with a therapeutically effective amount of a solid form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof, and enzalutamide, wherein the gene is selected from KLK2,FKBP5, TMPRSS2, KLK3, NCAPD3, NKX3-1, NDRG1, STEAP4, FAM105A, AKAP12,PMEPA1, PLPP1, SNA12, ACSL3, ERRFl1, CDC6, ELL2, CENPN, RHOU, EAF2,SGK1, SLC16A6, TIPARP, IGF1R, CCND1, ADAMTS1, or PRR15L. In oneembodiment, the androgen receptor modulator is a solid form of CompoundI.

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerafter treatment with a solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof, and determining, inthe sample, the expression level of an androgen receptor driven genes,where if the gene expression level, when compared to a referencestandard level, is decreased before or after treatment with a solid formof Compound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof, then proceeding with or resuming treatment of the subjectwith a therapeutically effective amount of the solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereof.In a specific embodiment, enzalutamide may be co-administered as secondtherapeutic agent. In another specific embodiment, the gene is selectedfrom KLK2, FKBP5, TMPRSS2, KLK3, NCAPD3, NKX3-1, NDRG1, STEAP4, FAM105A,AKAP12, PMEPA1, PLPP1, SNA12, ACSL3, ERRFl1, CDC6, ELL2, CENPN, RHOU,EAF2, SGK1, SLC16A6, TIPARP, IGF1R, CCND1, ADAMTS1, or PRR15L.

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerafter treatment with an androgen receptor modulator, and determining, inthe sample, the expression level of an androgen receptor driven genes,where if the gene expression level, when compared to a referencestandard level, is decreased before or after treatment with the androgenreceptor modulator, then proceeding with or resuming treatment of thesubject with a therapeutically effective amount of a solid form ofCompound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof, wherein the gene is selected from one or more selectedfrom the group consisting of KLK2, FKBP5, TMPRSS2, KLK3, NCAPD3, NKX3-1,NDRG1, STEAP4, FAM105A, AKAP12, PMEPA1, PLPP1, SNA12, ACSL3, ERRFl1,CDC6, ELL2, CENPN, RHOU, EAF2, SGK1, SLC16A6, TIPARP, IGF1R, CCND1,ADAMTS1, and PRR15L. In one embodiment, the androgen receptor modulatoris a solid form of Compound I or a pharmaceutically acceptable salt,solvate, or solvate salt thereof.

In one embodiment, the present disclosure provides a method for treatinga subject having a cancer, comprising, obtaining a sample of the cancerafter treatment with a solid form of Compound I or a pharmaceuticallyacceptable salt, solvate, or solvate salt thereof, and determining, inthe sample, the expression level of an androgen receptor driven genes,where if the gene expression level, when compared to a referencestandard level, is decreased before or after treatment with a solid formof Compound I or a pharmaceutically acceptable salt, solvate, or solvatesalt thereof, then proceeding with or resuming treatment of the subjectwith a therapeutically effective amount of the solid form of Compound Ior a pharmaceutically acceptable salt, solvate, or solvate salt thereof,wherein the gene is selected from one or more selected from the groupconsisting of KLK2, FKBP5, TMPRSS2, KLK3, NCAPD3, NKX3-1, NDRG1, STEAP4,FAM105A, AKAP12, PMEPA1, PLPP1, SNA12, ACSL3, ERRFl1, CDC6, ELL2, CENPN,RHOU, EAF2, SGK1, SLC16A6, TIPARP, IGF1R, CCND1, ADAMTS1, and PRR15L.

In one embodiment of the methods disclosed herein, cancer is selectedfrom prostate cancer, breast cancer, ovarian cancer, endometrial cancer,or salivary gland carcinoma. In one embodiment, the cancer is prostatecancer. In one embodiment, the prostate cancer is selected fromprimary/localized prostate cancer, locally advanced prostate cancer,recurrent prostate cancer, metastatic prostate cancer, advanced prostatecancer, metastatic castration-resistant prostate cancer (CRPC), orhormone-sensitive prostate cancer. In other embodiments, the prostatecancer is a metastatic castration-resistant prostate cancer. In someembodiments, the prostate cancer is androgen-dependent prostate canceror androgen-independent prostate cancer. In another embodiment, thecancer is breast cancer.

In one embodiment of any one of the methods disclosed herein, theandrogen receptor modulator is a solid form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof. Inone embodiment, the solid form of Compound I is crystalline Form A. Inone embodiment, the solid form of Compound I is an amorphous form. Inone embodiment, the solid form of Compound I is Material B, C, or D.

In one embodiment of any one of the methods disclosed herein, theandrogen receptor driven gene is an androgen receptor full-length drivengene. In one embodiment, the androgen receptor driven gene is anandrogen receptor V7 driven gene.

In one embodiment of any one of the methods disclosed herein, the genewith an abnormal activity is selected from KLK2, FKBP5, TMPRSS2, KLK3,NCAPD3, NKX3-1, NDRG1, STEAP4, FAM105A, AKAP12, PMEPA1, PLPP1, SNA12,ACSL3, ERRFl1, CDC6, ELL2, CENPN, RHOU, EAF2, SGK1, SLC16A6, TIPARP,IGF1R, CCND1, ADAMTS1, or PRR15L. See WO 2020/198710, which is herebyincorporated by reference in its entirety.

Having now generally described the invention, the same will be morereadily understood through reference to the following examples, whichare provided by way of illustration and are not intended to be limitingof the present invention.

EXAMPLES

The disclosure now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention

General Procedures—Analytical Methods

X-Ray Powder Diffraction (XRPD)

Figures labeled “Image by PatternMatch v3.0.4” were generated usingunvalidated software. XRPD patterns were collected with a PANalyticalX'Pert PRO MPD diffractometer or a PANalytical Empyrean diffractometerusing an incident beam of Cu radiation produced using an Optix long,fine-focus source. An elliptically graded multilayer mirror was used tofocus Cu Kα X-ray radiation through the specimen and onto the detector.Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzedto verify the observed position of the Si (111) peak is consistent withthe NIST-certified position. A specimen of the sample was sandwichedbetween 3-μm-thick films and analyzed in transmission geometry. Abeam-stop, short antiscatter extension, and antiscatter knife edge, wereused to minimize the background generated by air. Soller slits for theincident and diffracted beams were used to minimize broadening fromaxial divergence. Diffraction patterns were collected using a scanningposition-sensitive detector (X'Celerator) located 240 mm from thespecimen and Data Collector software v. 5.5. The data acquisitionparameters for each pattern are displayed above the image (X'Pert PROMPD) or within the Data Viewer v. 1.8 image (Empyrean) of each patternin the Data section of this report.

XRPD Indexing

The high-resolution XRPD patterns were indexed using proprietary SSCIsoftware (Triads™, see U.S. Pat. No. 8,576,985) or X'Pert High ScorePlus 2.2a (2.2.1) in this study. Indexing and structure refinement arecomputational studies. Agreement between the allowed peak positions,marked with red bars, and the observed peaks indicates a consistent unitcell determination. Successful indexing of the pattern indicates thatthe sample is composed primarily of a single crystalline phase. Spacegroups consistent with the assigned extinction symbol, unit cellparameters, and derived quantities are tabulated below each figureshowing tentative indexing solution. To confirm the tentative indexingsolution, the molecular packing motifs within the crystallographic unitcells must be determined. No attempts at molecular packing wereperformed.

Thermogravimetry (TGA) and TGA/DSC Combo Analysis

TGA and TGA/DSC Combo analyses were performed using a Mettler-ToledoTGA/DSC3+ analyzer. Temperature and enthalpy adjustments were performedusing indium, tin, and zinc, and then verified with indium. The balancewas verified with calcium oxalate. The sample was placed in an openaluminum pan. The pan was hermetically sealed, the lid pierced, theninserted into the TG furnace. A weighed aluminum pan configured as thesample pan was placed on the reference platform. The furnace was heatedunder nitrogen. The data acquisition parameters are displayed in theimages in the Figure section or Data section of this report.

Temperature Modulated Differential Scanning Calorimetry (TMDSC)

TMDSC was performed using Mettler-Toledo DSC3+ differential scanningcalorimeter. TOPEM® overlays the isothermal or ramped temperature with atime series of random temperature pulses of different durations. A taulag adjustment is performed with indium, tin, and zinc. The temperatureand enthalpy are adjusted with octane, phenyl salicylate, indium, tinand zinc. The adjustment is then verified with octane, phenylsalicylate, indium, tin, and zinc. The sample was placed into ahermetically sealed aluminum DSC pan, and the weight was accuratelyrecorded. The pan lid was pierced then inserted into the DSC cell. Aweighed aluminum pan configured as the sample pan was placed on thereference side of the cell. The data was collected from −50° C. to 160°C. with a modulation amplitude of ±0.25° C. and a 15 to 30 second periodwith an underlying heating rate of 2° C./minute.

Single Crystal X-Ray Diffraction (SCXRD)

1. Preparation of the Single Crystal Sample: A solution of Compound I inacetone was prepared and filtered through a 0.2-μm nylon filter into aclean glass vial covered with perforated foil. The sample was allowed toevaporate slowly to dryness at ambient temperature. A single crystal wascarefully removed from the vial wall for analysis.

2. Data Collection: A colorless plate having approximate dimensions of0.28×0.12×0.04 mm3, was mounted on a polymer loop in random orientation.Preliminary examination and data collection were performed on a RigakuSuperNova diffractometer, equipped with a copper anode microfocus sealedX-ray tube (Cu Kαλ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixelarray detector. Cell constants and an orientation matrix for datacollection were obtained from least-squares refinement using the settingangles of 6525 reflections in the range 4.7930°<θ<77.0370°. The spacegroup was determined by the program CRYSALISPRO (CrysAlisPro1.171.38.41r, Rigaku Oxford Diffraction, 2015) to be P2₁/c(international tables no. 14). The data were collected to a maximumdiffraction angle (2θ) of 155.124° at room temperature.

3. Data Reduction: Frames were integrated with CRYSALISPRO. A total of13457 reflections were collected, of which 5294 were unique. Lorentz andpolarization corrections were applied to the data. The linear absorptioncoefficient is 3.352 mm⁻¹ for Cu Kα radiation. An empirical absorptioncorrection using CRYSALISPRO was applied. Transmission coefficientsranged from 0.789 to 1.000. Intensities of equivalent reflections wereaveraged. The agreement factor for the averaging was 2.22% based onintensity.

4. Structure Solution and Refinement: The structure was solved by directmethods using SHELXT (see Sheldrick, G. M. Acta Cryst. 2015, A71, 3-8).The remaining atoms were located in succeeding difference Fouriersyntheses. The structure was refined using SHELXL-2014 (see Sheldrick,G. M. Acta Cryst. 2008, A64, 112-122; Id.). Hydrogen atoms residing onnitrogen were refined independently. Hydrogen atoms residing on carbonwere included in the refinement but restrained to ride on the atom towhich they are bonded. The structure was refined in full-matrixleast-squares by minimizing the function:

Σw(|F_(o)|²−|F_(c)|²)²

where the weight, w, is defined as 1/[σ²(F_(o) ²)+(0.1009P)²+(0.9289P)],where P=(F_(o) ²+2F_(c) ²)/3. Scattering factors were taken from the“International Tables for Crystallography” (International Tables forCrystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, TheNetherlands, 1992, Tables 4.2.6.8 and 6.1.1.4.). Of the 5294 reflectionsused in the refinements, only the reflections with intensities largerthan twice their uncertainty [I>2□(I)], 4317, were used in calculatingthe fit residual, R. The final cycle of refinement included 351 variableparameters, 15 restraints, and converged with respective unweighted andweighted agreement factors of:

R = ΣF_(o) − F_(c)/Σ F_(o) = 0.0559$R_{w} = {\sqrt{\left( {\Sigma\;{w\left( {F_{o}^{2} - F_{c}^{2}} \right)}^{2}\text{/}\Sigma\;{w\left( F_{o}^{2} \right)}^{2}} \right)} = 0.1711}$

The standard deviation of an observation of unit weight (goodness offit) was 1.05. The highest peak in the final difference Fourier had anelectron density of 0.674 e/Å³. The minimum negative peak had a value of−0.649 e/Å³.

5. Calculated X-ray Powder Diffraction (XRPD) Pattern: A calculated XRPDpattern was generated for Cu radiation using MERCURY (Macrae, C. F.Edgington, P. R. McCabe, P. Pidcock, E. Shields, G. P. Taylor, R. TowlerM. and van de Streek, J. J. Appl. Cryst., 2006, 39, 453-457) and theatomic coordinates, space group, and unit cell parameters from thesingle crystal structure.

6. Atomic Displacement Ellipsoid and Packing Diagrams: The atomicdisplacement ellipsoid diagram was prepared using MERCURY. Atoms arerepresented by 50% probability anisotropic thermal ellipsoids.

Abbreviations

Abbreviations/Acronyms Full Name/Description agg. Aggregates B/EBirefringence/extinction B Birefringence d Day(s) FC Fast cooling FDFreeze drying (lyophilization) FE Fast evaporation h Hour(s) LIMSLaboratory information management system ppt Precipitation RE Rotaryevaporation RT Room temperature SC Slow cooling SE Slow evaporationT_(g) Glass transition temperature UM Unknown morphology VF Vacuumfiltration v/v Volume/Volume

Example 1: Synthesis and Characterization of Crystalline Form A ofN-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamideN-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide(Compound I)

Step 1: A mixture of 4-(chloromethyl)-2-methylsulfanyl-pyrimidine (1)(324 mg, 1.86 mmol),3-chloro-2-(2-chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile(2) (0.5 g, 1.43 mmol) and K₂CO₃ (493 mg, 3.57 mmol) in MeCN (4 mL) wasstirred at 80° C. for 5 hrs. LCMS and HPLC showed the reaction wascompleted and 81.4% of the desired product formed. The resulting mixturewas quenched with sat.NH₄Cl (10 mL) and extracted with EtOAc (10 mL×3).The combined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by MPLC to give3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile(3) (0.54 g, yield: 77.4%) as colorless syrup. ¹H NMR (400 MHz, CDCl₃)δ=8.54 (d, J=4.8 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz,1H), 7.22 (d, J=5.2 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz,2H), 5.09 (s, 2H), 4.43 (t, J=6.4 Hz, 2H), 3.88 (t, J=6.4 Hz, 2H), 2.59(s, 3H), 1.65 (s, 6H). after work up: HPLC (220 nm): 94.7%. LCMS (220nm): 93.5%. Exact Mass: 487.1; found 488.0/490.0.

Step 2: To a suspension of3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (3) (1.07 g, 2.19 mmol) in THF (20 mmL)was added a suspension of Oxone (5.39 g, 8.76 mmol) in water (20 mL) at20° C. The mixture was stirred at 20° C. for 16 hrs. LCMS and HPLCshowed the reaction was completed and 93.0% of the desired productformed. The resulting mixture was quenched with sat.Na₂SO₃. The aqueouslayer was extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(methylsulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4) (1.04 g, yield: 91.2%) ascolorless syrup. ¹H NMR (400 MHz, CDCl₃) δ=8.94 (d, J=4.8 Hz, 1H), 7.85(d, J=4.8 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.15(d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.30 (s, 2H), 4.43 (t, J=6.4Hz, 2H), 3.88 (t, J=6.0 Hz, 2H), 3.40 (s, 3H), 1.66 (s, 6H). IPCdetection: HPLC (220 nm): 92.956%. LCMS (220 nm): 93.0%. Exact Mass:519.1; found 520.1/522.1.

Step 3: A suspension of3-chloro-2-(2-chloroethoxy)-5-(2-(4-((2-(methylsulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4) (30 mg, 0.058 mmol),methanesulfonamide (11 mg, 0.12 mmol) and K₂CO₃ (15.9 mg, 0.12 mmol) inMeCN (2 mL) was stirred at 85° C. for 5 hrs. LCMS showed the reactionwas completed and 91.6% of the desired product formed. The resultingmixture was partitioned between EtOAc (2 mL) and aq.NH₄Cl (2 mL). Theaqueous layer was extracted with EtOAc (2 mL×3). The combined organiclayers were washed with brine (2 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give Compound I, Form A (40 mg)as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.77 (br s, 1H), 8.64 (d,J=4.8 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.29 (d,J=5.2 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.11 (s,2H), 4.43 (t, J=6.0 Hz, 2H), 3.88 (t, J=6.0 Hz, 2H), 3.48 (s, 3H), 1.65(s, 6H). IPC detection: LCMS (220 nm): 91.6% purity. Exact Mass: 534.1;found 535.1/537.2.

XRPD spectrum was obtained for Form A as shown in FIG. 1 and Tables1A-1B. The sample likely contains small amount of NaCl. The sharp peaksat 27.3±0.2 and at 31.7±0.2 degrees two-theta is consistent with thepresence of NaCl. Form A was determined successfully in this study, andthe results indicate it is an anhydrous/unsolvated material.

TGA/DSC thermograms were also obtained for Form A as shown in FIG. 2. ByTGA, a weight loss of 2.2 wt % was observed from 50-230° C., which islikely due to the loss of residual solvents in the sample. The dramaticchange in the slope of the thermogram starting at about 284° C. (onset)is likely associated with the decomposition of the material. By DSC, anendotherm is observed at approximately 182° C. (onset), which could bedue to the melting of the material.

DVS (dynamic vapor sorption) analysis was carried out on Form A (Table2, FIG. 3). The DVS profile of Form A displayed a total of 5.474% weightgain during sorption from 5% to 95% RH, with the majority of the weightgain occurred above 55% RH (1.978 wt % gain from 55% to 85% RH and 3.106wt % gain from 85% RH to 95% RH). During desorption from 95% RH to 5%RH, the sample displayed 5.472% weight loss, and some hysteresis wasobserved from 95% to 25% RH. The DVS data suggest that Form A exhibitslow hygroscopicity within 5%-55% RH, limited hygroscopicity within55%-85% RH, and significant hygroscopicity within 85%-95% RH.

Solids recovered after DVS analysis was consistent with Form A by XRPDanalysis.

TABLE 2 DVS Isotherm Analysis Sorp Mass Desorp Mass Target Sample ChangeSample Change Hyster- RH (%) RH (%) (%) RH (%) (%) esis Cycle 1 5.0 4.90.000 5.4 0.002 15.0 15.4 0.055 16.1 0.068 0.013 25.0 24.9 0.111 25.60.146 0.036 35.0 34.5 0.169 35.3 0.277 0.108 45.0 44.8 0.242 45.6 0.7160.474 55.0 54.5 0.390 55.5 1.040 0.650 65.0 64.6 0.986 65.6 1.438 0.45275.0 74.5 1.567 75.5 1.931 0.364 85.0 84.7 2.368 85.8 2.972 0.604 95.096.0 5.474 96.0 5.474

Example 2: Solubility Experiments and Polymorph Screening Experiments

The approximate solubility of Compound I in various organic solvents wasdetermined by adding solvent aliquots to weighed samples Compound I.Weighed samples of Compound I were treated with aliquots of the testsolvents or solvent mixtures at ambient temperature. Completedissolution of the test material was determined by visual inspection.Solubility was estimated based on the total solvent volume used toprovide complete dissolution. The actual solubility may be greater thanthe value calculated because of the use of solvent aliquots that weretoo large or due to a slow rate of dissolution. If complete dissolutionwas not achieved during the experiment, the solubility is expressed as“less than” (<). If complete dissolution was achieved by only onealiquot addition, the value is reported as “larger than” (>).

A summary of the approximate solubility of Compound I in various organicsolvents is provided in Table 3.

TABLE 3 Approximate Solubility of Compound I Solubility Observationafter Solvent (mg/mL) (a) Initial Observation Storage (48 h) acetone 5.3 (c) — — ACN 2.04 (c) — — DCM 20 clear amber solution clear brownsolution dioxane >107 (b)  clear brown solution settled solids DMA >79 clear brown solution clear amber solation DMSO  >12 (c) — — Et₂O <2cloudy off-white settled solids suspension EtOAc 1.97 (c) — — EtOH 0.17(c) — — iPrOAc <1 cloudy off-white settled solids suspension MEK  6clear amber solution clear yellow/amber solution MeOH 0.21 (c) — — MTBE<1 cloudy white suspension settled solids NMP >117  clear brown solutionclear brown solution THF 54 clear amber solution fine yellow suspensiontoluene <1 cloudy beige solution settled solids (a): Unless otherwisespecified, solubilities are estimated at ambient temperature andreported to the nearest mg/mL; if complete dissolution was not achieved,the value is reported as “<”; if complete dissolution was achieved withone aliquot of solvent, the value is reported as “>”; the actualsolubility may be larger than the value calculated because of the use ofsolvent aliquots that were too large or due to a slow rate ofdissolution. (b): Based on observations during the screen on samples atmuch larger scales, the approximate solubility in p-dioxane is within35-103 mg/mL. (c): Equilibrium solubility data acquired at 24 hours.

Various method of polymorph screening was conducted as described below.

The slurry-trituration experiments were conducted by stirring Compound Iin specified organic solvents or solvent mixtures at varioustemperatures for 4-12 days. Sufficient amounts of solids of Compound Iwere added to selected solvents or solvent mixtures so that excesssolids remained. The mixtures were then triturated with stir bars atdesignated temperatures for specified periods of time. Solids wereisolated by centrifugation using Spin-X centrifuge tubes equipped with a0.45 μm nylon filter. Solids were air dried before analysis.

A summary of experimental conditions and results is included in Table 4.Based on XRPD analysis, all slurry-trituration experiments generatedsolids that are consistent with Form A of Compound I.

TABLE 4 Polymorph Screen of Compound I - Slurry-Trituration ExperimentsXRRB Solvent Conditions (a) Observation Result acetone  RT, 12 d beigesolution, beige solids Form A ACN  RT, 12 d beige solution, beige solidsForm A dioxane RT, 4 d suspension, beige solids; Form A analyzed wet 4:1(v/v) RT, 7 d beige solution, beige solids Form A dioxane/ heptane DCM RT, 12 d orange solution, Form A beige solids 2:1 (v/v) RT, 7 d beigesolution, beige solids Form A DCM/MeOH EtOAc  RT, 12 d beige solution,beige solids Form A MEK  RT, 12 d beige solution, beige solids Form ATHF RT, 5 d wet beige solids, dried Form A during analysis 1:1 (v/v) RT,7 d beige solution, beige solids Form A THF/MeOH iPrOAc 50° C., 7 d  beige solution, beige solids, Form A UM, B/E MTBE 50° C., 7 d   beigesolation, beige solids, Form A UM, minor B/E MeOH 50° C., 7 d   beigesolution, beige solids, Form A UM EtOH 50° C., 7 d   beige solution,beige solids, Form A UM, minor B/E toluene 50° C., 7 d   beige solution,beige solids, Form A UM (a): Temperatures and time are approximate.

To examine the propensity of Compound I to exist as hydrates, theslurry-trituration experiments were also conducted in selected aqueousmixtures with high water activities (A_(w)≥˜0.7). As shown in Table 5,all the water activity slurries generated Form A of Compound I.

TABLE 5 Polymorph Screen of Compound I - Water Activity Slurries Solvent(a) A_(w) (b) Conditions Observations XRPD Results acetone/H₂O 0.82 RT,9 d beige solids Form A (80/20) 50° C., 6 d   beige solids Form AHFIPA/H₂O 1.41 RT, 6 d beige solids Form A (80/20) DMF/H₂O 0.70 RT, 6 dbeige solids Form A (50/50) (a): Solvent ratios are approximate and byvolume. (b): Water activity values are approximate and represent thewater activity of the solvent system at 25° C. The activity coefficientcalculations are based on modeling the interactions between functionalgroups present in the components. These calculated water activity valueswere not verified experimentally.

Polymorph screening was performed using various solvent-based approachesincluding evaporation, cooling, solvent/anti-solvent addition, andcombinations of the techniques. For slow cooling (SC) and fast cooling(FS) experiments, saturated or concentrated solutions of Compound I wereprepared in selected solvents at elevated temperatures and filteredthrough pre-warmed 0.2-μm nylon filters (unless specified in Table 6)into pre-warmed clean vials at the temperature. Solutions were thenremoved from the heating plate and left at ambient conditions (FC), orallowed to cool to ambient temperature on the heating plate with heatturned off (SC). If no handleable amount of solids appeared in vials,samples were moved to sub-ambient conditions. If not handleable amountof solids appeared after sub-ambient storage, the experiment wasconverted to an anti-solvent addition experiment.

For solvent/anti-solvent addition (SAS) experiments, Sub-ambientsolutions from cooling attempts, or saturated/concentrated solutions ofCompound I prepared in selected solvents were filtered through 0.2-μmnylon filters into specified antisolvent at ambient temperature. Sampleswere either isolated immediately for analysis, or stirred at specifiedconditions before isolation. Detailed cooling and anti-solvent additionexperimental conditions, observations, and XRPD results are summarizedin Table 6.

When using dioxane as the solvent during solvent/anti-solvent additionattempts, it was observed that the choice of an anti-solventsignificantly impacts the experimental results. As detailed in Table 6,the addition of a dioxane solution into H₂O generated Form A, while theaddition into heptane or hexanes yielded Material B or Material D,respectively. Insufficient amount of solids were observed when a dioxanesolution was added into Et₂O. In all these attempts, the solvent ratiowas kept constant at 1:3 (v/v) of dioxane/anti-solvent.

TABLE 6 Polymorph Screen of Compound I - Cooling and Anti-SolventAddition XRPD Solvent (a) Conditions Observations Results 1:1acetone/heptane 1) API solution (e.g., 1) clear solution — Compound Isolution) in 10 2) clear solution mL acetone filtered into 10 mL heptane2) stirred, RT, 12 d (days) 1:2 ACN/H₂O 1) SC in ACN, 50° C. to RT, 1)clear solution Form A kept 3 d 2) clear yellow solution 2) kept at 2-8°C., 7 d 3) clear yellow solution 3) kept in freezer, 5 d 4) white cloudysolution, 4) added cold solution into wet beige solids, needles, H₂O,centrifuged B/E 1:3 dioxane/Et₂O 1) API solution in 3 mL 1) solutionbecame hazy but IS dioxane filtered into 9 mL no apparent solids Et₂O 2)solids observed 2). shaken then let sat on 3) no apparently increase inbench for 5 min solids amount 3) stirred, RT, 1 d 1:3 dioxane/heptane 1)API solution in 5 mL 1) immediate white ppt, pink Material B dioxanefiltered into 15 suspension mL heptane, shaken 2) pink solids, minorB/E, 2) VF UM 1) API solution in 5 mL 1) immediate white ppt, pinkMaterial B dioxane filtered into 15 suspension mL heptane, shaken 2)pink solids, needles, B/E; 2) centrifuged, analyzed wet analyzed wet 1)API solution in 5 mL 1) immediate white ppt, pink Material B dioxanefiltered into 15 mL suspension heptane, shaken 2) milky suspension,beige 2) stirred, RT, 3 d solids 1) API solution in 5 mL 1) whitesolids, needles Material B dioxane filtered into 15 mL & agg., B/Eheptane, shaken 2) stirred, RT, 15 d 1:3 dioxane/hexanes 1) API solutionin 3 mL 1) solution turned cloudy Material D dioxane filtered into 9 mLimmediately upon addition; hexanes; shaken solids on the side and 2)stirred, RT, 1 d; bottom centrifuged 2) beige solids; agg., UM, partialB; analyzed damp 1:3 dioxane/H₂O 1) API solution in 3 mL 1) immediateppt Form A dioxane filtered into 9 mL 2) beige solids; agg. of B/E H2Oparticles; analyzed wet 2) centrifuged 1:2 EtOAc/EtOH 1) SC in EtOAc,50° C. to RT 1) clear solution — 2) kept at 2-8° C., 4 d 2) clear yellowsolution 3) kept in freezer, 5 d 3) clear yellow solution 4) added coldsolution into 4) clear solution, no solids EtOH, centrifuged 1:3MEK/Et₂O 1) FC in MEK, 50° C. to RT 1) clear solution — 2) kept at 2-8°C., 7 d 2) clear yellow solution 3) kept in freezer, 5 d 3) clear yellowsolution 4) added cold solution into 4) clear solution, no solids Et₂O,centrifuged 1:3 THF/MeOH 1) FC in THF, 50° C. to RT 1) clear solution —2) kept at 2-8° C., 7 d 2) clear yellow solution 3) kept in freezer, 5 d3) clear yellow solution 4) added cold solution into 4) clear solution,no solids MeOH, centrifuged 3:10 THF/hexanes 1) API solution in 2 mLTHF 1) immediate white ppt Form A filtered into 10 mL hexanes 2) pinksolids, B/E, UM 2) VF (a) Solvent ratios are by volume. MEK = methylethyl ketone

Evaporation studies were conducted. For fast evaporation (FE) and slowevaporation (SE), solutions of Compound I were prepared in selectedsolvents and filtered through 0.2-μm nylon filters into clean glassvials, and allowed to evaporate at ambient temperature from open vials(FE) or from vials covered with perforated aluminum foil (SE). Fastevaporation was assisted with a steady flow of N₂ gas where indicated.Detailed experimental conditions, observations, and XRPD results forevaporation studies are summarized in Table 7.

TABLE 1A XRPD Table of Form A of Compound I °2θ d space (Å) Intensity(%)  5.19 ± 0.20 17.013 ± 0.655  41  9.60 ± 0.20 9.206 ± 0.191 8 10.42 ±0.20 8.483 ± 0.162 6 10.89 ± 0.20 8.118 ± 0.149 12 12.38 ± 0.20 7.144 ±0.115 6 12.94 ± 0.20 6.836 ± 0.105 51 13.17 ± 0.20 6.715 ± 0.101 6 13.52± 0.20 6.544 ± 0.096 15 15.40 ± 0.20 5.749 ± 0.074 13 15.64 ± 0.20 5.661± 0.072 7 15.90 ± 0.20 5.569 ± 0.070 5 16.17 ± 0.20 5.477 ± 0.067 1316.75 ± 0.20 5.289 ± 0.063 7 17.01 ± 0.20 5.208 ± 0.061 8 17.48 ± 0.205.069 ± 0.058 100 17.80 ± 0.20 4.979 ± 0.055 32 18.74 ± 0.20 4.731 ±0.050 38 19.57 ± 0.20 4.532 ± 0.046 23 20.20 ± 0.20 4.392 ± 0.043 920.78 ± 0.20 4.271 ± 0.041 70 21.80 ± 0.20 4.074 ± 0.037 73 22.59 ± 0.203.933 ± 0.034 23 22.99 ± 0.20 3.865 ± 0.033 18 23.29 ± 0.20 3.816 ±0.032 14 23.53 ± 0.20 3.778 ± 0.032 7 24.91 ± 0.20 3.572 ± 0.028 1025.28 ± 0.20 3.520 ± 0.027 23 25.82 ± 0.20 3.448 ± 0.026 5 26.21 ± 0.203.397 ± 0.025 9 26.57 ± 0.20 3.352 ± 0.025 19 27.29 ± 0.20 3.265 ± 0.02312 27.83 ± 0.20 3.203 ± 0.023 14 28.06 ± 0.20 3.177 ± 0.022 13 28.68 ±0.20 3.110 ± 0.021 4 29.09 ± 0.20 3.067 ± 0.021 5 29.59 ± 0.20 3.016 ±0.020 10 29.95 ± 0.20 2.981 ± 0.019 25

The majority of the experimental conditions for polymorph screeninggenerated solids that are consistent with Form A.

Example 3: Observation of Materials B, C, and D in Polymorph ScreeningExperiments

As shown in Example 2, multiple solvent/anti-solvent attempts wereperformed in 1:3 (v/v) dioxane/heptane (Table 6), which consistentlyproduced Compound I in a form labeled as Material B. See FIG. 4 for XRPDspectrum of Material B. Indexing attempts on XRPD pattern of Material Bwere not successful.

Material B was found to be unstable upon drying (Table 8), and thereforeit was not further characterized. A mixture of Form A and Material C wasobtained when Material B was dried at 65-66° C. under vacuum. See FIG. 4for XRPD spectrum of Material C with Form A. When dried at ambientconditions on a filter paper, Material B converted to a disorderedMaterial C. Based on experimental conditions to generate Material B andits drying studies, without being bound to any theory, Material B couldbe a solvated material which can convert to Material C upon drying.

TABLE 8 Drying Study on Material B Material Conditions (a) ObservationsXRPD Results Material B 65-66° C., beige solids. UM, B Material C +vacuum. 5 d Form A Material B RT, on filter beige solids, UM disorderedpaper, 3 d Material C + peaks Material D 50-52° C., beige solids, UM,Form A vacuum, 3 d partial B (a): Temperatures and time are approximate.

In order to evaluate the relative stability between Form A and MaterialC, a competitive slurry was performed. About equal amounts (by mass) ofMaterial C (mixture w/ some Form A) and Form A were added to acetone sothat solids persisted and were stirred at room temperature for 9 days.Solids were isolated by centrifugation using Spin-X centrifuge tubesequipped with a 0.45 μm nylon filter. Beige solids were observed. ByXRPD, the post-slurry solids are consistent with a pure phase of Form Aindicating Form A is more stable than Material C under the examinedcondition. Material C could be an anhydrous material.

Material D was observed in 1:3 (v/v) dioxane/hexanes bysolvent/anti-solvent addition followed by ambient slurry for 1 day(Table 5). Based on visual observations, Material D and Material Bappear to have some similarity in their XRPD patterns. See FIG. 4 forXRPD spectrum of Material D. Indexing attempts on XRPD pattern ofMaterial D were not successful.

Further analyses, including ¹H NMR and TGA/DSC were performed onMaterial D. The ¹H NMR spectrum of Material D is consistent with theprovided chemical structure of Compound I. Based on the NMR spectrum,Material D contains about 0.9 mol/mol of dioxane and trace amount ofhexanes.

The TGA/DSC thermograms of Material D are shown in FIG. 5. By TGA, astep-like weight loss is observed with an onset at about 93° C.,indicating Material D is a solvated material. The sample displays aweight loss of 13.6 wt % within 48-125° C., corresponding to ˜0.96 molesof dioxane, which is consistent with the NMR data. The DSC thermogramshows an endotherm at about 90° C. (onset), which is consistent with theTGA step-like weight loss and is likely due to desolvation of MaterialD. Upon further heating, a sharp endotherm is observed at 182° C.(onset), which could be due to melting of Form A. Material D likelyconverts to Form A upon desolvation.

The endotherm observed at 182° C. is likely due to Form A meltingbecause Material D was observed to desolvate into Form A by XRPD whendried at 50-52° C./vacuum conditions for 3 days (FIG. 6). Based oncharacterization data and the drying result, without being bound to anytheory, Material D is likely a solvated material of Compound I.

Example 4. Amorphous Form of Compound I

Variety of solvent-based techniques, including rotary evaporation andlyophilization, were carried out to screen for an amorphous form ofCompound I. Experimental conditions, observations, and XRPD results aredetailed in Table 9.

TABLE 9 Experiments to Screen for an Amorphous Form of Compound I XRPDSolvent Condition Observation Result DCM 1) dissolved 198 mg 1) clearorange x-ray in 20 mL DCM, solution amorphus + filtered NaCl 2) RE @ 63°C. 2) beige solids, some B noticed, but mostly no B 3) secondary dried3) — @ vacuum, RT, 1 d 1) dissolved 205 mg 1) clear orange disordered in20 mL DCM, solution Form A filtered 2) RE @ 61° C. 2) beige solids 3)secondary dried 3) beige glassy @ vacuum, RT, 3 d solids dioxane 1) FD,6 d 1) white fluffy disordered solids, no B, UM

Rotary evaporation experiments were performed using DCM as a solvent.Dilute solutions of Compound I were prepared in DCM and filtered through0.2-μm nylon filters into a clear round bottom flasks. The flasks wereattached to a rotary evaporator and immersed in a water bath atspecified temperatures and DCM was rapidly evaporated to dryness undervacuum. The samples underwent secondary drying under vacuum at roomtemperature in a vacuum oven before XRPD testing.

The sample generated from the first rotary evaporation experiment wassecondary dried at ambient temperature under vacuum for 1 day and thenanalyzed by XRPD. By XRPD, the sample displays broad halos withcrystalline peaks due to NaCl, indicating successful generation of anamorphous form of Compound I (“x-ray amorphous”). See FIG. 7, thirdspectrum from bottom.

Materials described as “x-ray amorphous” are typically characterizedfurther by thermal analysis where the appearance of a glass transition(T_(g)) provides support for the non-crystalline nature of the material.Temperature modulated DSC was performed on the material to investigatethe T_(g) (Table 10). As shown in FIG. 8, T_(g) was observed atapproximately 61° C. as a step change in the reversing heat flow signal.On further heating, an exotherm likely due to crystallization wasobserved at about 91° C. (peak). The endotherm at about 178° C. (onset)could be, without bound to any theory, due to melting of thecrystallized material, which could be Form A based on crystallizationstudy (Table 11). The endotherm has a slightly lower temperature thanthe endotherm observed for Form A (182° C., FIG. 2), which could be dueto the specimen containing an amorphous or disordered portion (i.e., notcompletely crystallized during the analysis).

TABLE 10 Analysis of Selected Material Material Analysis Results (a)Form A SCXRD crystal structure successfully determined Material D ¹H NMRconsistent with the chemical structure of EPI-7386; contains dioxane(~0.9 mol/mol) and trace hexanes TGA/DSC TGA: 13.6 wt % loss from48-125° C. 93° C. (step, onset) 276° C. (decomp. onset) DSC: 90° C.(endo, onset) 182° C. (endo, onset) x-ray ¹H NMR consistent with thechemical amorphous structure of EPI-7386; |contains w/NaCl) trace DCM(~0.004 mol/mol) TGA 1.0 wt % loss from 45-200° C. 280° C. (decomp.onset) TMDSC Reversing heat flow: 61° C. (T_(g), midpoint) ΔCp 0.4 J/g·°C. Total heat flow: 91° C. (exo, peak) 178° C. (endo, onset) (a):Temperatures from DSC and TGA are rounded to the whole numbers; ΔCp andwt % from TGA are rounded to one decimal place.

TABLE 11 Crystallization Study of Amorphous or Disordered forms ofCompound I Starting XRPD Solvent Material Conditious (a) ObservationsResults — Amorphous 1) stored at RT, 1) minor B disordered desiccator,10 d Form A acetone Disordered 1) stirred, RT, 4 d 1) white solids FormA H₂O 1) stirred, RT, 4 d 1) white solids Form A (a): Times areapproximate.

Further analyses including ¹H NMR and TGA were also collected on thisamorphous sample (Table 10). The ¹H NMR spectrum was consistent with thechemical structure of Compound I and contains trace amount of DCM. ByTGA (FIG. 9), about 1.0 wt % loss is observed from 45-200° C., which islikely due to the residual DCM and moisture in the material. Thedramatic change in the slope of the TGA thermogram starting at 280° C.(onset) is likely associated with the decomposition of the material.This amorphous form of Compound I was observed to become disordered FormA upon ambient storage in a desiccator for about 10 days (FIG. 10, topspectrum), indicating amorphous Compound I is physically not stable andcrystallizes into Form A at ambient temperature. A repeated rotaryevaporation attempt from DCM solution generated disordered Compound IForm A (FIG. 7, second spectrum from bottom) after the sample wassecondary dried at ambient temperature under vacuum for 3 days, whichprovides further evidence that amorphous Compound I is not physicallystable.

One lyophilization experiment targeting amorphous Compound I wasperformed from a diluted solution in dioxane. A dilute solution ofCompound I in dioxane was prepared and flash frozen by filtering itthrough a 0.2-μm nylon filter into a clean glass flask in dropwise. Theglass flask was pre-cooled to −78° C. in a dry ice/acetone bath. Thesample was attached to a Labconco FreeZone 71040 BenchtopFreeze Dryerand lyophilized for 6 days.

The resulting solids were found to be disordered Compound I by XRPD(FIG. 7, bottom spectrum). Crystallization studies were performed onthis disordered material (Table 10) and solids were stirred in acetoneand H₂O for 4 days at ambient conditions. Both experiments generatedcrystalline Form A (FIG. 10, bottom two spectra).

Solubility: Generally, the solubility of an amorphous form is higherthan that of the corresponding crystal form, due to the lack ofcrystalline lattice forces in the amorphous state. Solubility of theamorphous form of Compound I was studied by slow addition of theamorphous form from an organic stock solution into the pH 6.5phosphate-buffered saline (PBS) solution or 0.5% wt simulated intestinalfluid (SIF) in pH 6.5 PBS. When the amorphous solubility is reached, adrug-rich phase forms which typically scatters light (e.g.,liquid-liquid phase separation or LLPS), which can be detected byscattering of UV/Visible light and/or by dynamic light scattering (DLS).

No scattering event prior to crystallization was observed. Based on thedata obtained, the amorphous solubility in pH 6.5 PBS and 0.5% SIF (pH6.5) was >2.5 μg/mL and >25 μg/mL, respectively (FIG. 16). While anexact concentration could not be determined in this test, the amorphoussolubility appears to be at least 20× higher than the crystallinesolubility in simulated intestinal media. FIG. 16 shows concentration(solids lines) and scattering (dotted lines) vs. time during addition ofa 95:5 THF:Water solution of amorphous form of Compound I into blank PBSor 0.5% SIF in PBS.

Example 5. Single Crystal Structure Determination for Form a of CompoundI

During the screen, single crystals of Form A were observed by slowevaporation from an acetone solution (Table 7). A suitable singlecrystal was therefore selected and analyzed by single-crystal X-raydiffractometry, and the structure of Form A was determined successfully.

The crystal system is monoclinic and the space group is P2₁/c. The cellparameters and calculated volume are: a=17.5550(2) Å, b=10.96169(13) Å,c=13.7961(2) Å, α=90°, β=104.5717(15)°, γ=90°, and V=2569.40(6) Å³. Inone embodiment, single crystals of Form A has a density of about 1.384g/cm³. The molecular weight is 535.43 g/mol with Z=4, resulting in acalculated density of 1.384 g/cm³. Standard uncertainty is written incrystallographic parenthesis notation, e.g. 0.123(4) is equivalent to0.123±0.004.

The quality of the structure obtained was high, as indicated by the fitresidual, R, of 0.0559 (5.59%). R-factors in the range 2%-6% are quotedto be the most reliably determined structures (Glusker, Jenny Pickworthet al. Crystal Structure Analysis: A Primer, 2^(nd) ed.; OxfordUniversity press: New York, 1985; p. 87). The asymmetric unit wasdetermined to contain one Compound I molecule. The cyano and chlorinemoieties on the phenyl ring were found to be rotationally disordered by180°, refining to 78% in the predominant orientation. The calculatedXRPD pattern of Form A from the single crystal data is shown in FIG. 11,along with the experimental pattern acquired (see Example 1).

Example 6. Activity of Exemplary Compounds in Cellular Assays

LNCaP cells were transiently transfected with the PSA (6.1kb)-luciferase reporter for 24 h, and then treated with indicatedconcentration of representative compounds with synthetic androgen, R1881(1 nM) for 24 h. After 24 h of incubation with R1881, the cells wereharvested, and relative luciferase activities were determined. Todetermine the IC₅₀, treatments were normalized to the maximum activitywith androgen-induction (in the absence of test compounds, vehicle only)(Table 12).

Luciferase Assay: Lysates were thawed on ice then collected intoV-bottom 96-well tissue culture plates. Lysates were centrifuged at 4°C. for 5 minutes at 4000 rpm. To measure luminescence of LNCaP celllysates the Firefly Luciferase Assay System (Promega) was employed,according to manufacturer's protocol.

Statistical analyses were performed using GraphPad Prism (Version 6.01for Windows; La Jolla, Calif., USA). Comparisons between treatment andcontrol groups were compared using Two-Way ANOVA with post-hoc Dunnett'sand Tukey's tests. Differences were considered statistically significantat P values less than 0.05. Densitometric quantification of relative ARlevels was determined by Image.

Reference Compound X and EPI-002 have the following structures:

The PSA-Luc % inhibition IC₅₀ values Compound I is shown in Table 12.

TABLE 12 IC₅₀ of Compound I on Androgen-Induced PSA-Luciferase ActivityAndrogen-induced PSA-luciferase Compound ID IC₅₀ (nM) n X 1054 3Compound I 535 2 EPI-002 9580 2 Enzalutamide 189 8 Bicalutamide 306 2

Cell Proliferation Assay: Cell proliferation/viability was measured inLNCaP and PC3 cells with Alamar blue, and proliferation was measured inLN-CaP95 cells with BrdU incorporation. In LNCaP cells, AR specificproliferation is calculated by measuring the difference between controlcells treated with or without 0.1 nM R1881. See Table 13.

TABLE 13 IC₅₀ of Compound I on Cell Proliferation/Viability CellularProliferation/Viability IC50 (μM) Compound ID LNCaP PC-3 LNCaP95 X3.00 >10 4.00 Compound I 0.44 >10 3.78 EPI-002 9.00 >10 ~20 Enzalutamide0.35 >10 >10

Example 7: In Vivo Activity of Representative Compounds in LNCaPXenografts Model

Tumor growth was measured in male NCG mice bearing LNCaP tumors.Castration was performed when tumors reached ˜100 mm³ and dosing (60mg/kg PO qd) started 1 week after castration. Body weight of the micewere captured biweekly in the animals which showed no drug relatedtoxicity. Individual tumor volume change from baseline measured at theend of the experiment. See FIG. 12. Data demonstrated that therepresentative compounds showed activity and induced partial regressionsof tumor growth. The C_(min) at 5 mg/kg PO and extrapolated C_(min) inefficacy of the representative compounds are shown in Table 14.

TABLE 14 C_(min) at 5 mg/kg PO and C_(min) at 5 mg/kg PO Cmin at Cmin atCompound 5 mg/kg PO 5 mg/kg PO ID (μM) (μM) Compound I 0.68 8.18Enzalutamide 3.80 22.8

Example 8: Solid Dispersion Composition Study 1

Compound I has very low crystalline solubility and very high amorphoussolubility enhancement. It crystallizes rapidly from supersaturatedaqueous solutions, dosed alone or with pre-dissolvedprecipitation-inhibiting polymers. Amorphous form of Compound I has amoderate glass transition temperature (Tg=62° C.) and partiallyre-crystallizes during heating of the amorphous form (Class 2 glassformer).

Based on these characteristics, compositions were prepared at 10% activeloading with 5 different polymers or polymer blends (Table 15). Allmanufactured formulations were amorphous by x-ray powder diffraction(XRPD).

TABLE 15 Compositions SDD Yield Potency No. Compositions (%) (mgA/g) A10/90 Compound I/HPMCAS-H 93 104 ± 0.1 B 10/80/10 CompoundI/HPMCAS-H/Soluplus 96 107 ± 0.1 C 10/90 Compound I/HPMCAS-L 94 102 ±0.3 D 10/90 Compound I/PVP K30 91 106 ± 0.3 E 10/90 Compound I/EudragitL100 95 102 ± 0.1 mgA/g = milligrams of Compound I per gram of SDDcomposition

Five spray dried dispersion (SDD) compositions were successfullymanufactured with high yields on a Bend Lab Dryer with 35 kg/hr dryingcapacity (BLD-35). All SDDs were sprayed at the same atomizationpressure (120 psig). After spray drying, the SDDs were secondary driedin a heating vacuum tray dryer for about 24 hours to remove residualsolvent. Manufacturing parameters are listed in Table 16.

TABLE 16 SDD composition manufacturing summary Batch size (g) 3 Solvent(w/w) 9/1 DCM/methanol Solids Content (wt %) 4 Atomizer Schtick 2.0Drying Gas Flow Rate (g/min) 500 Solution Flow-rate (g/min) ~35Atomization Pressure (psig) 120 Inlet Temperature (° C.) 71 (for SDD-A);77 (for SDD-B to SDD-E) Outlet Temperature (° C.) 35

All SDDs contained amorphous form of Compound I by X-ray diffractionanalysis (FIG. 13). The Tg of each SDD was dominated by the type ofpolymer as determined by modulated differential scanning calorimetry(mDSC). A water or solvent loss peak is observed for each SDD, beingmost intense for SDD composition D (FIG. 14). The solid lines of themDSC thermograms of FIG. 14 are the reverse heat flow and the dashedlines are the non-reversing heat flow. Summary of the mDSC data islisted in Table 17.

TABLE 17 Tabulated mDSC data for SDD compositions SDD No. Tg (° C.) ΔCp(J/(g° C.)) A 99 ± 0.5 0.33 ± 0.02 B 97 ± 0.6 0.33 ± 0.03 C 98 ± 0.20.34 ± 0.02 D 145 ± 0.03 0.29 ± 0.01 E 176 ± 2.0  0.41 ± 0.10

Example 9: Solid Dispersion Composition Study 2

SDD compositions G-M of Compound I were successfully manufactured withhigh yields on a Bend Lab Dryer with 35 kg/hr drying gas capacity(BLD-35) (Table 18). All SDDs were sprayed at the same atomizationpressure (120 psig). After spray drying, the SDDs were secondary driedin a heating vacuum tray dryer at 40° C. for about 23 hours to removeresidual solvent. Manufacturing parameters are listed in Table 19.

Secondary Drying was monitored by headspace gas chromatography in aseparate tray drying space for an SDD composition of Table 18. Prior tosecondary drying (wet sample), residual solvent in the SDD compositionof Table 18 at storage temperature of 5° C. and 30° C. in sealed,stainless steel containers. Some solvent loss during storage and/orsampling was observed. SDD dried quickly during secondary drying,falling below ICH limits for residual DCM (600 ppm limit and permitteddaily exposure of 6.0 mg/day) in less than 2 hours. Data supportssecondary drying step of about 6 hours.

All manufactured formulations (stored at 2-8° C. after manufacturing)were amorphous by x-ray powder diffraction (XRPD), exhibiting theexpected amorphous halo with no evidence of crystalline Compound I aftermanufacturing.

TABLE 18 SDD Compositions SDD Yield Potency No. Compositions (%) (mgA/g)A¹ 10/90 Compound I/HPMCAS-H 93 104 ± 0.1 G 15/85 Compound I/HPMCAS-H 95157 H 20/80 Compound I/HPMCAS-H 94 209 I 25/75 Compound I/HPMCAS-H 96261 J 30/70 Compound I/HPMCAS-H 93 314 K 60/40 Compound I/Eudragit L10091 616 L 20/70/10 Compound I/PVP-VA64/Soluplus 91 215 M 20/80 CompoundI/Soluplus 101 210 ¹From Example 8. mgA/g = milligrams of Compound I pergram of SDD composition

TABLE 19 SDD composition manufacturing summary Batch size (g) 5-10 gSolvent (w/w) 9/1 DCM/methanol Solids Content (wt %) 4 Atomizer Schtick2.0 Drying Gas Flow Rate (g/min) 500 Solution Flow-rate (g/min) ~35Atomization Pressure (psig) 120 Inlet Temperature (° C.) 90 (SDD-G); 85(SDD-H and SDD-I); 84 (SDD-J); 76 (SDD-K); 75 (SDD-L and SDD-M) OutletTemperature (° C.) 35

Tg of selected SDD compositions were determined by modulateddifferential scanning calorimetry (mDSC). The dry Tg (Tg determinedunder dry conditions) decreased with increased loading of Compound I.The dry Tg of all the SDD compositions showed sufficiently high forstorage under dry conditions Table 20. The Tg decreased at elevated RHdue to plasticization by absorbed water. SDD compositions I and Kabsorbed about 3% water at 75% RH while SDD composition M absorbed about6% water, which is consistent with the decrease in Tg at 75% RH observedfor SDD composition M.

TABLE 20 Tabulated mDSC data for SDD compositions SDD Dry 75% RH Waterat No. Tg (° C.) Tg (° C.) 75% RH (wt %) A 101.2 — — G 91.6 — — H 89 — —I 79.4 60.3 3 K 67.5 58.4 3 M 69.8 28.9 6

Example 10: Solid Dispersion Composition Study 3

SDD compositions H-J and N-R of Compound I were successfullymanufactured with high yields on a Bend Lab Dryer with 35 kg/hr dryinggas capacity (BLD-35) (Table 21). All SDDs were sprayed at the sameatomization pressure (120 psig). After spray drying, the SDDs weresecondary dried in a heating vacuum tray dryer at 40° C. with 3 litersper minute or 2.5 liters per minute of N₂ sweep gas for about 18.5-23hours to remove residual solvent. Manufacturing parameters are listed inTable 22.

TABLE 21 SDD Compositions Residual Residual SDD Yield Potency MeOH DCMNo. Compositions (%) (mgA/g) (wt %) (wt %) H 20/80 Compound 82 210 ND NDI/HPMCAS-H I 25/75 Compound 85 260 ND ND I/HPMCAS-H J 30/70 Compound 96310 ND ND I/HPMCAS-H N 35/65 Compound 95 360 ND ND I/HPMCAS-H O 40/60Compound 96 410 ND 0.01 I/HPMCAS-H P 45/55 Compound 93 450 <LOQ 0.03I/HPMCAS-H Q 50/50 Compound 93 500 <LOQ 0.06 I/HPMCAS-H R 75/25 Compound93 750 <LOQ 0.09 I/HPMCAS-H mgA/g = milligrams of Compound I per gram ofSDD composition; LOQ = limit of quantification

TABLE 22 SDD composition manufacturing summary Batch size (g) 1-15 gSolvent (w/w) 9/1 DCM/methanol Solids Content (wt %) 4 Atomizer Schtick2.0 Drying Gas Flow Rate (g/min) 500 Solution Feed Rate (g/min) 30-44Atomization Pressure (psig) 120 Inlet Temperature (° C.) 92 (SDD-H andSDD-N); 100 (SDD-I); 97 (SDD-J); 89 (SDD-O); 85 (SDD-P, SDD-Q, andSDD-R) Outlet Temperature (° C.) 40-42

All manufactured formulations (stored at 2-8° C. after manufacturing)were amorphous by x-ray powder diffraction (XRPD), exhibiting theexpected amorphous halo with no evidence of crystalline Compound I aftermanufacturing (FIG. 15).

The patents and publications listed herein describe the general skill inthe art and are hereby incorporated by reference in their entireties forall purposes and to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofany conflict between a cited reference and this specification, thespecification shall control. In describing embodiments of the presentapplication, specific terminology is employed for the sake of clarity.However, the invention is not intended to be limited to the specificterminology so selected. Nothing in this specification should beconsidered as limiting the scope of the present invention. All examplespresented are representative and non-limiting. The above-describedembodiments may be modified or varied, without departing from theinvention, as appreciated by those skilled in the art in light of theabove teachings. It is therefore to be understood that, within the scopeof the claims and their equivalents, the invention may be practicedotherwise than as specifically described.

1. A crystalline form of Compound I:

or a pharmaceutically acceptable salt, solvate, or solvate salt thereof.2. The crystalline form of claim 1, wherein Compound I is anhydrous ornon-solvated.
 3. The crystalline form of claim 1, wherein Compound I isnot present as a pharmaceutically acceptable salt.
 4. The crystallineform of claim 1 which exhibits an X-ray powder diffraction (XRPD)pattern comprising peaks at about 17.48±0.2, 20.78±0.2, and 21.80±0.2degrees two-theta.
 5. The crystalline form of claim 4, wherein the XRPDpattern further comprises peaks at about 5.19±0.2 and 12.94±0.2 degreestwo-theta.
 6. The crystalline form of claim 4, wherein the XRPD patternfurther comprises at least two peaks selected from about 17.80±0.2,18.74±0.2, 19.57±0.2, 22.59±0.2, 25.28±0.2, or 29.95±0.2 degreestwo-theta.
 7. The crystalline form of claim 4 which exhibits an XRPDpattern comprising peaks in Table 1B.
 8. (canceled)
 9. The crystallineform of claim 1, which is Form A exhibiting an XRPD patternsubstantially similar to FIG. 1, provided that peaks at 27.3±0.2 and31.7±0.2 degrees two-theta are excluded.
 10. The crystalline form ofclaim 1 which exhibits a differential scanning calorimetry (DSC)thermogram comprising an endotherm peak which onset at about 182° C. 11.The crystalline form of claim 1 which exhibits a thermogravimetricanalysis (TGA) thermogram comprising a change in slope which onset atabout 284° C.
 12. The crystalline form of claim 1, wherein thecrystalline form has a purity in the range of about 80% to about 99%.13. The crystalline form of claim 1, wherein the crystalline form has apurity of about 95% or higher.
 14. The crystalline form of claim 1,wherein the crystalline form has a purity of about 99% or higher.15.-36. (canceled)
 37. A composition comprising a crystalline form ofclaim 1 and a pharmaceutically acceptable carrier.
 38. The compositionof claim 37, wherein the crystalline form is Form A.
 39. The compositionof claim 37, further comprising an amorphous form of Compound I or apharmaceutically acceptable salt, solvate, or solvate salt thereof. 40.(canceled)
 41. (canceled)
 42. The composition of claim 37, furthercomprising one or more additional therapeutic agents. 43.-52. (canceled)53. A crystalline form of Compound I:


54. A composition comprising a crystalline form of claim 53 and apharmaceutically acceptable carrier.